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J 



Europaisches Patentamt 
European Patent Office 
Office europeen des brevets 



© Publication number: 
EUROPEAN PATENT APPLICATION 



0 471 236 A1 



© Application number: 91112798.3 


Int CI s A61K 31/435 Afi1K^1/44 


\ [~\ Iri r\i filing- OA H"7 Q4 

uate ot THing. ou.Uf.yi 


L/U / U 4/1 /U4 




® Priority: 30.07.90 JP 202963/90 


6-1, Taniguchisono-machi, Ukyo-ku 


30.07.90 JP 202964/90 


Kyoto 616(JP) 


27.05.91 JP 121277/91 


Inventor: Kozai, Yoshio 


12.06.91 JP 140186/91 


9-5, Seifuso 1-chome 


® Date of publication of application: 


Toyonaka, Osaka 564(JP) 


Inventor: Tomimatsu, Kiminori 


19.02.92 Bulletin 92/08 


E-104, 7 Nyoidani 3-chome 


® Designated Contracting States: 


Minoo, Osaka 562(JP) 


Inventor: Shibouta, Yumlko 


AT BE CH DE DK ES FR GB GR IT LI LU NL SE 


601, 30-20, Deguchi-cho 


© Applicant: TAKEDA CHEMICAL INDUSTRIES, 


Suita, Osaka 546(JP) 




LTD. 




3-6, Doshomachi 2-chome Chuo-ku 


© Representative: Lederer, Franz, Dr. et al 


Osaka 541 (JP) 


Lederer, Keller & Riederer, Patentanwalte, 


@ Inventor: Takatani, Muneo 


Lucile-Grahn-Strasse 22 


W-8000 Munchen 80(DE) 



< 

CD 



@ Imidazopyridine derivatives and their use. 

© A calmodulin inhibitory composition containing a compound of the formula (I): 




(i) 

X-A-B 

as well as an angiogenesis inhibitory composition containing a compound of the formula (1): 



Q_ 
LU 



S- A'-N-C00R d 
i 



f 



i 



n 



EP 0 471 236 A1 



FIELD OF THE INVENTION 

The present invention relates to imidazopyridine derivatives and their use. Particularly, it relates to 
imidazo[1 ,2-a]pyridine derivatives which are useful as medicines and a calmodulin inhibitor containing the 
5 same. 

BACKGROUND OF THE INVENTION 

Recently, various cerebrovascular or cardiovascular ischemic diseases have been increased with 

70 increasing in population of people of advanced age. At present, as one of medicines for treating these 
diseases, a calcium channel blocker has been widely used clinically and, therefore, cerebrovascular 
disorders caused by hypertension are decreased. However, it is said that cardiac ischemic disorders are not 
decreased, and development of medicines having superior mechanism of activities has been desired. 

On the other hand, it has been reported that chlorpromazine having an inhibitory activity to calmodulin 

75 which is an intracellular calcium-binding protein is effective for experimental ischemic disorders [G.E. 
Thomas, S. Levitsky and H. Feinberg, J. Med. Cell Cardiol., 15, 621 (1983); J.I. Dahlager and T. Bilde, 
Scand. J. Urol Nephrol., 10, 126 (1976); and K.R. Chien, J. Adams, R.G. Pfan and J.L. Farber, Am. J. 
Pathol., 88, 539 (1977)], and it is also said that calmodulin plays an important role in ischemic disorders 
[S.W. Schaffer, R.S. Roy and J.M. McMcord, Eur. Heart J., 4 (Suppl. H), 81 (1983)]. However, 

20 phenothiadines such as chlorpromazine have a strong central depressant activity and, therefore, there is a 
drawback in the use thereof as a medicine for circulatory system. Therefore, development of a more 
superior calmodulin inhibitor has been desired. 

There are lot of reports relating to imidazo[1 ,2-a]pyridine derivatives. However, there is few reports 
about pharmacological activities of compounds wherein a hydrocarbon having a functional group is bound at 

25 the 5-position through S, S(O), S(0)2, O or N. For example, European Patent Application P871 081 89.9 
reports such compounds as starting materials for synthesis of cephem compounds. Japanese Patent Laid 
Open Publication Nos. 277393/1987 and 10792/1988 report them as cephem compounds. EP-A-6614 and 
DE2820938 report them as hypotensors. However, none of them discloses calmodulin inhibitory activity. 

30 OBJECTS OF THE INVENTION 

Under these circumstances, the present inventors have intensively studied about activities and synthe- 
sis of imidazo[1 ,2-a]pyridine derivatives wherein a hydrocarbon group having a functional group is bound at 
the 5-position through S, S(O), S(0) 2 , O or N. As a result, certain derivatives having excellent calmodulin 
35 inhibitory activities have been found. Thus, the present invention has been completed. 

SUMMARY OF THE INVENTION 

According to the present invention, there is provided a calmodulin inhibitory composition comprising a 
40 compound of the formula (I): 



so wherein X is S, S(O), S(0) 2 , O or NR 3 (wherein R 3 is a hydrogen or an optionally substituted hydrocarbon 
group); A is a divalent Ci-is hydrocarbon group which may contain an ethereal oxygen at any possible 
position and may have a substituent at a branched part of the hydrocarbon group; B is an acylated amino 
group or an acylated or etherified hydroxyl group and the nitrogen atom of the amino group of B may form 
a ring together with the carbon atom of A or R 3 ; R 1 and R 2 are the same or different and are hydrogen, an 

55 optionally substituted hydrocarbon group, halogen, nitro group, nitroso group, an optionally protected amino 
group, a lower alkoxycarbonyl group or a lower alkyl carbamoyl group, or a salt thereof (including a 
solvate). 



45 




(I) 



X-A-B 



2 



9NS0OCID: <EP. 



0471236A1 J > 



EP 0 471 236 A1 



DETAILED DESCRIPTION OF THE INVENTION 



In the formula (I), X is S. S(O), S(0)2, 0 or NR 3 (wherein R 3 is a hydrogen or an optionally substituted 
hydrocarbon group). Preferably, X is S or O. Examples of the optionally substituted hydrocarbon group 
5 represented by R 3 include a lower alky I group, an aralkyl group and the like. 

Examples of the divalent Ci-is hydrocarbon group which may contain an ethereal oxygen at any 
possible position and may have a substituent at a branched part of the hydrocarbon group represented by 
A include a group represented by the formula: 



70 



75 



R R R° 

I I I 

-<C)i-<C) m -(C) n - 
U U la 



wnerein I, m and n are integers of 0 to 5, respectively; R\ R 5 , R 6 , R 7 , R 8 and R 9 are hydrogen, an 
optionally substituted lower alkyl, aralkyl or aryl group, respectively; and R* and R 5 , R 5 and R 7 or R 8 and 
R 9 may bind together to form a ring, or R 4 or R 6 may bind together with R 8 or R 9 to form a ring, a group 
20 represented by the formula: 



-CH2CH2OCH2CH2", 



or a group represented by the formula: 



25 



30 



/Tlx- (CH 2 )p- 
-(CH,)o-<£j? 



wherein o and p are integers of 0 to 5, respectively. 

Examples of the optionally substituted hydrocarbon group represented by R 1 and R 2 include an 
optionally substituted lower alkyl, aralkyl or aryl group. 

Examples of the acylated amino group represented by B include a group represented by the formula: 

35 -NR 10 R 11 [wherein R 10 is hydrogen, an optionally substituted alkyl, aralkyl or aryl group, or a group 
represented by the formula: -CO-R 12 (wherein R 12 is hydrogen, or an optionally substituted alkyl, aralkyl or 
aryl group), -S0 2 R 13 (wherein R 13 is an optionally substituted alkyl, aralkyl or aryl group), -CO-NR 14 R 15 - 
(wherein R 14 and R 15 are hydrogen, or an optionally substituted alkyl, aralkyl or aryl group and R u and R 15 
may bind together to form a ring) or -CS-NR 14 R 15 (wherein R u and R 15 are as defined above); R 11 is a 

40 group represented by the formula: -CO-R 15 (wherein R 1& is an optionally substituted alkyl, aralkyl or aryl 
group, -CO-OR 10 (wherein R 16 is as defined above), -SO2R 17 (wherein R 17 is an optionally substituted alkyl, 
aralkyl or aryl group), -CO-NR u R 15 (wherein R 14 and R 15 are as defined above) or -CS-NR 14 R 15 (wherein 
R 1 * and R 15 are as defined above); and R 10 may bind together with R 3 , R\ R 6 . R 8 , R 11 , R 16 or R 17 to form 
a ring]. Examples of the acylated or etherificated hydroxyl group include a group represented by the 

45 formula: -O-R 18 [wherein R 18 is an optionally substituted alkyl, aralkyl or aryl group, or a group represented 
by the formula: -CO-NR 14 R 15 (wherein R 14 and R 15 are as defined above) or -CO-R 19 (wherein R 19 is an 
optionally substituted alkyl, aralkyl or aryl group]. 

As the lower alkyl group in each substituent in the formula (!) for example there is a straight or 



l-iyi, <- - uuiui iy .. o-uutuny: •_; ;ru 1 Kb i nu iuwtjf a.iKyi y;uup nay n.avu 1 to *1 substituents suet", at naiogen, 
nitro, amino, lower alkylammo, cyclic amino, lower alkoxy, aryloxy, carbamoyl, cyano, hydroxy, carboxy, 
lower alkoxycarbony!, lower alkoxycarbamoy! and the like. Examples of halogen include fluorine, bromine, 
55 chlorine and icdine. 

K' . . r: r : t; \.N-Oia 1 * <i' v "';' ■■. Li 1 . ' w r i f .r a Kyi mcLVv "ic;S 1 \v 6 rarer; r at-" rr, z such 



EP 0 471 236 A1 



dimethylamino, diethylamino, dibutylamino, methylethytamino and the like. 

Examples of the cyclic amino group as the above substituent include a 4 to 7 membered cyclic amino 
group such as N-pyrrolidinyl, piperidino, piperaziny-l, morpholino, homopiperazino and the like. 

Examples of the lower alkoxy group as the above substituted include a straight or branched alkoxy 
5 group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy and the 
like. 

Examples of the aryloxy group as the above substituent include a C&-10 aryloxy group such as 
phenoxy, 1-naphthoxy, 2-naphthoxy group and the like. 

Examples of the lower alkoxycarbonyl group as the above substituent include an alkoxycarbonyl group 
70 of which alkoxy moiety has 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl propoxycar- 
bonyl, butoxycarbonyl and the like. 

Examples of the lower alkylcarbamoyl group as the above substituent include a N-monoalkylcarbamoyl 
group of which alkyl moiety has 1 to 6 carbon atoms such as methylcarbamoyl, ethylcarbamoyl, propylcar- 
bamoyl, butylcarbamoyl and the like, and a N,N-dialkylcarbamoyl group of which alkyl moiety has 1 to 6 
75 carbon atoms such as dimethylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, methylethylcarbamoyl and 
the like. 

As the alkyl group in the formula (I), for example, there are a straight or branched alkyl group having 1 
to 30, preferably 1 to 10 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, 
nonyl, decyl, undecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, 
20 eicosanyl, heneicosanyl, docosanyl, tricosanyl, tetracosanyl, pentacosanyl, hexacosanyl, heptacosanyl, 
octacosanyl, nonacosanyl, triacontanyl, farnesyl, dihydrophytyl and the like; a cycloalkyl group having 3 to 8 
carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like; 
an saturated bicyclic hydrocarbon group formed by binding 5 to 8 membered rings to each other such as 
norbornyl, bicyclo[2.2.2.]octyl, bicyc!o[3.3.1 ]nonyl, bicyclo[3.3.0]octyl, perhydropentalenyl, perhydroindenyl, 
25 perhydroazulenyl, perhydrocyclopentacyclooctenyl, perhydronaphthyl, perhydrobenzocycloheptenyl, per- 
hydrobenzocyclooctenyl, perhydroheptalenyl, perhydrocycloheptacyclooctenyl and the like; and a saturated 
tricyclic hydrocarbon group formed by binding 5 to 8 membered rings to each other such as adamantyl- 
perhydroindacenyl (as, s), perhydroacenaphthylenyl, perhydrophenanthryl, perhydroanthryl and the like. 
The above alkyl group may have an unsaturated bond, and examples of the alkyl having an unsaturated 
30 bond include an alkenyl group having 2 to 30 carbon atoms such as vinyl, allyl, 9-octadecenyl and the like; 
a cycloalkenyl group having 5 to 8 carbon atoms such as cyclopentenyl, cyclohexenyl and the like; an 
unsaturated bicyclic hydrocarbon group such as bicyclo[2.2.2]oct-2-enyl, indanyl (e.g. 1-indanyl, 2-indanyl, 
etc.), indenyl (e.g. 1H-inden-1-yl, 1H-inden-2-yl, 1 H-inden-3-yl, etc.), dihydronaphthyl (e.g. 1 ,2-dihydro-1- 
naphthyl, 1 ,2-dihydro-2-naphthyl, etc.). tetrahydronaphthyi (e.g. 5,6,7,8-tetrahydro-l-naphthyl, 5,6,7,8- 
35 tetrahydro-2-naphthyl, etc.), 5H-benzocycloheptenyl (5H-5-benzocycloheptenyl, 5H-8-benzocycloheptenyl t 
etc.), dihydro-5H-benzocycloheptenyl (e.g. 6,7-dihydro-5H-8-benzohydrocycloheptenyl, etc.), tetrahydroben- 
zocyclooctenyl (e.g. 5,6,7,8-tetrahydro-9-benzocyclooctenyl, etc.) and the like; and an unsaturated tricyclic 
hydrocarbon group such as acenaphthenyl (e.g. 1-acenaphthenyl, etc.), tetrahydroanthryl (e.g. 1,2,3,4- 
tetrahydro-1-anthryl, etc.) and the like. 
40 The above alkyl group having 1 to 30 carbon atoms and alkenyl group having 2 to 30 carbon atoms 
may be substituted with about 1 to 4, preferably 1 or 2 substituents such as cycloalkyl group having 3 to 8 
carbon atoms (e.g., cyclopropyl, etc.), phenyl, naphthyl, halogen (e.g., Br, CI, etc.), cyano, oxo, lower alkoxy 
group having 1 to 6 carbon atoms and the like. The phenyl group as the substituent for the alkyl and alkenyl 
group may be substituted with 1 to 4 substituents such as lower alkyl group having 1 to 6 carbon atoms, 
45 lower alkoxy group having 1 to 6 carbon atoms, hydroxy, nitro, halogen and the like. 

The cycloalkyl group, bicyclic hydrocarbon group, tricyclic hydrocarbon group and groups having an 
unsaturated bond thereof included in the alkyl group may be substituted with 1 to 4, preferably 1 or 2 
substituents such as lower alkyl group, halogeno lower alkyl group, hydroxy lower alkyl group, acyloxy 
lower alkyl group, lower alkoxy-lower alkyl group, lower alkoxy group, halogeno lower alkoxy group, lower 
50 alkoxycarbonyl-lower alkoxy group, lower alkenyloxy group, aralkyloxy group, lower alkoxy-lower alkoxy 
group, lower alkoxycarbonyl group, carboxy group, carbamoyl group, N,N-di lower alkylcarbamoyl group, fol- 
lower alkylcarbamoyl group, halogen, cyano, nitro, hydroxy, acyloxy group, amino group, lower alkylsul- 
fonylamino group, acylamino group, lower alkoxycarbonylamino group, acyl group, mercapto, lower alkylthio 
group, lower alkylsulfinyi group, lower alkylsulfonyl group, oxo and the like. When they are substituted with 
55 2 or more substituents, the substituents may be the same or different. 

Examples of the lower alkyl group as the above substituent include an alkyl group having 1 to 6 carbon 
atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. 

As the halogeno lower alkyl group, for example, there is an alkyl group having 1 to 6 carbon atoms 

4 

BNSDCCID: <EP 0471236A1 1 > 



EP 0 471 236 A1 

which is substituted with 1 to 3 halogen atoms such as trifluoromethyl, fluoromethyl, chloroethyl, fluoroethyl 
and the like. 

As the hydroxy lower alky i group, for example, there is a hydroxyalkyl group having 1 to 6 carbon 
atoms such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and the like. 
5 As the acyloxy lower alkyl group, for exampe, there is an alkyl group having 1 to 6 carbon atoms which 

is substituted with a lower alkanoyloxy or benzoyloxy group having 2 to 6 carbon atoms such as 
acetoxyethyl, benzoyloxyethyl and the like. 

As the lower alkoxy-lower alkyl group, for example, there is an alkyl group having 1 to 6 carbon atoms 
which is substituted with an alkoxy group having 1 to 6 carbon atoms such as methoxyethyl, ethoxyethyl, 
70 propoxyethyl, butoxyethyl, methoxypropyl, methoxybutyl, ethoxypropyl, ethoxybutyl and the like. 

As the lower alkoxy group, for example, there is an alkoxy group having 1 to 6 carbon atoms such as 
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. 

As the halogeno lower alkoxy group, for example, there is an alkoxy group having 1 to 6 carbon atoms 
which is substituted with 1 to 3 halogen atoms such as chloroethoxy, fluoroethoxy, difluoroethoxy, 
75 trifluoroethoxy, chloropropoxy, chlorobutoxy and the like. 

As the lowftr alkoxycarbonyl-lower alkoxy group, for example, there is an alkoxy group having 1 to 6 
carbon atoms which is substituted with an alkoxycarbonyl group of which alkoxy moiety has 1 to 6 carbon 
atoms such as methoxycarbonylmethoxy, ethoxycarbonylmethoxy, butoxycarbonylmethoxy, methoxycar- 
bonylpropoxy, ethoxycarbonylethoxy and the like. 
20 As the lower alkenyloxy group, for example, there is an alkenyloxy group having 2 to 6 carbon atoms 

such as vinyloxy, allyloxy, butenyloxy and the like. 

As the aralkyloxy group, for example, there is a phenyl lower alkyloxy group of which lower alkyl moiety 
has 1 to 6 carbon atoms such as benzyloxy, phenethyloxy, 3-phenylpropyloxy, a-methylphenethyloxy, a- 
methylbenzyloxy, a-ethylbenzyloxy, /9-ethylphenethyloxy, /3-methylphenethyloxy and the like. 
25 As the lower alkoxy-lower alkoxy group, for example, there is an alkoxy group having 1 to 6 carbon 

atoms which is substituted with an alkoxy group having 1 to 6 carbon atoms such as ethoxymethoxy, 
methoxyethoxy, butoxyethoxy, ethoxypropoxy and the like. 

As the lower alkoxycarbonyl, for example, there is an alkoxycarbonyl group having 1 to 6 carbon atoms 
of which alkoxy moiety has 1 to 6 carbon atoms such as methoxy carbony I, ethoxycarbonyl, propoxycar- 
30 bonyl, butoxycarbonyl and the like. 

As the N,N-di lower alkylcarbamoyl group, for example, there is a N,N-dialkylcarbamoyl group of which 
alkyl moiety has 1 to 6 carbon atoms such as N.N-dimethylcarbamoyl, N.N-diethylcarbamoyl, N,N- 
dipropylcarbamoyl, N.N-dibutylcarbamoyl, N-ethyl-N-methylcarbamoy! and the like and a N,N-di lower 
alkylcarbamoyl group of which alkyl moieties bound together to form 5 or 6 membered ring structure (e.g. 
35 N-pyrrolidinylcarbonyl, piperidinocarbonyl, etc.). 

As the N-lower alkylcarbamoyl group, for example, there is a N-alkylcarbamoyl group of which alkyl 
moiety has 1 to 6 carbon atoms such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N- 
butylcarbamoyl and the like. 

Examples of halogen include chloro, fluoro, bromo, and iodo. 
40 As the acyloxy group, for example, there is an alkanoyloxy group having 2 to 6 carbon atoms such as 

acetoxy, propanoyloxy, butyloxy, pivaloyloxy and the like, and benzoyloxy group. 

As the lower alkylsulfonylamino group, for example, there is an alkylsulfonylamino group having 1 to 6 
carbon atoms such as methanesulfonylamino, ethanesulfonylamino and the like. 

As the acylamino group, for example, there is an alkanoylamino having 2 to 6 carbon atoms such as 
45 acetamide, propanoylamino, butylylamino, pivaloylamino and the like, and benzamide group. 

As the lower alkoxycarbonylamino group, for example, there is an alkoxycarbonylamino group of which 
alkoxy moiety has 1 to 6 carbon atoms such as methoxycarbonylamino, ethoxycarbonylamino, propoxycar- 



as methylthio, ethyltnio, propylthio, outyltnto ana tne Iiko. 

As the lower aikylsulfinyl group, for example, there is an afky Isulfiny I group having 1 to 6 carbon atoms 
such as methylsulfinyi, ethylsulfinyl. propylsulfinyl. butylsulfinyl and the like. 



EP 0 471 236 A1 



a naphthyl-lower alkyi of which alkyl moiety has 1 to 6 carbon atoms such as (l-naphthyl)methyl, 2-(1- 
naphthyl)ethyl, 2-(2-naphthyl)ethyl and the like. 

The phenyl moiety of the phenyl-lower alkyl group and the naphthy! moiety of the naphthyl lower alkyl 
group may be substituted with 1 to 4 substituents such as halogen, lower alkyl group, lower alkoxy group, 
5 nitro, cyano, hydroxy, lower alkoxycarbonyl group, carbamoyl group, lower aikylcarbamoyl group and the 
like. 

Examples of halogen include fluoro, bromo, chloro and iodo. As the lower alkyl group, for example, 
there is the same lower alkyl group as that in the above formula (I). 

As the lower alkoxy group, for example, there is a straight or branched alkoxy group having 1 to 6 
io carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy and the like. 

As the lower alkoxycarbonyl group, for example, there is an alkoxycarbonyl group having 1 to 6 carbon 
atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like. 

As the lower aikylcarbamoyl group, for example, there is a N-alkylcarbamoyl group of which alkyl 
moiety has 1 to 6 carbon atoms such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcar- 
15 bamoyl and the like, and a N,N-dialkylcarbamoyl group of which alkyl moiety has 1 to 6 carbon atoms such 
as dimethylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, methylethylcarbamoyl and the like. 

As the aryl group in the formula (I), that having 4 to 24 carbon atoms is preferred. For example, there is 
an aromatic monocyclic, bicyclic or tricyclic hydrocarbon group such as phenyl, 1 -naphthyl, 2-naphthyl, 
phenanthryl, anthryl and the like, and an aromatic monocyclic or bicyclic heterocyclic group such as thienyl, 
20 fury!, benzothienyl, benzofuranyl and the like. 

The aryl group may be substituted with 1 to 4, preferably 1 or 2 substituents such as halogen, lower 
alkyl group, lower alkoxy group, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl group, carbamoyl, 
lower aikylcarbamoyl group and the like. 

Examples of halogen include fluoro, bromo, chloro and iodo. 
25 As the lower alkyl group, for example, there is an alkyl group having 1 to 6 carbon atoms, or the lower 

alkyl group may have an unsaturated bond. 

As the lower alkyl group having an unsaturated bond, for example, there is a lower alkenyl group having 
2 to 6 carbon atoms. 

As the alkyl group having 1 to 6 carbon atoms and the lower alkenyl group having 2 to 6 carbon atoms, 
30 for example, there is the same group as the lower alkyl group in the above formula (I). 

Examples of the lower alkoxy group include an alkoxy group having 1 to 6 carbon atoms, examples of 
the lower alkoxycarbonyl group include an alkoxycarbonyl group of which alkoxy moiety has 1 to 6 carbon 
atoms, and examples of the lower aikylcarbamoyl group include a N-alkylcarbamoyl group of which alkyl 
moiety has 1 to 6 carbon atoms and a N.N-dialkylcarbamoyl group of which alkyl moiety has about 1 to 6 
35 carbon atoms. Examples of these groups include the same groups as the lower alkoxy, lower alkoxycar- 
bonyl and lower aikylcarbamoyl substitutents of the phenyl moiety in the above aralkyl group. 

As the aryl group containing oxo, for example, there are benzoquinolyl, naphthoquinolyl, anthraquinolyl 
and the like. 

Examples of halogen in FT and R 2 include fluoro, bromo, chloro and iodo. 
40 As the lower alkoxycarbonyl group and the lower aikylcarbamoyl group in R 1 and R 2 , for example, there 
is the same groups as the lower alkoxycarbonyl and lower aikylcarbamoyl substituents on the phenyl 
moiety of the above aralkyl group. 

Examples of the group wherein R 10 and R 3 are bound together to from a ring include that a group 
represented by the formula: 




50 

wherein q is 2 or 3, and A is as defined above. 

Examples of the group wherein R 10 is bound with R\ R 6 or R 8 to form a ring include a group 
represented by the formula: 

55 



6 



BNSDOCID: <EP D47i 236A1 I. > 



EP 0 471 236 A1 



lCH 2»^ NR ll _„„ J (CH 2»<I 



NR ~ CH 2\ NR 

(CH 2 ) r ^ , (CH 2 ) r ^ 



-CH 2 CH 2 -( ' NR 



(CH 2 )/ 



wherein q and r are 2 or 3, respectively; and R" is as defined above. 

Examples of the group wherein -NR 10 R" forms a ring in B include a group represented by the formula: 

0 0 o 



V V" w 

0 , 



I I 



D> 0> CO 1 - 



o 2 




-9 jo -o 

/ 0 ' 

3Q-Q -n 



and the like. 

The above hetero ring may be substituted with 1 to 4, preferably 1 or 2 substituents such as lower alkyl 
group, halogeno lower alkyl group, hydroxy lower alkyl group, acyloxy lower alkyl group, lower alkoxy-lower 
alkyl group, lower alkoxy group, halogeno lower alkoxy group, lower aikoxycarbonyl-lower alkoxy group, 
lower alkenyloxy group, aralkyloxy group, lower alkoxy-lower alkoxy group, lower alkoxycarbonyl group, 
carboxy group, carbamoyl group, N.N-di lower alkylcarbamoy! group, N-lower alkylcarbamoyl group, 
halogen, cyano. nitro, hydroxy, acyloxy group, amino, lower alkylsulfonylamino group, acylamino group. 



atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, teii-butyl and the like. 

As the halogeno lower alkyi group, fcr example, there is an afky! group having 1 to 6 carbon atoms 

wn'rh >s substituted with 1 to 3 haJocers sue** 1 as *nf!uoromet h v' fluorc rn ethyi. ch'com^t^v' rH'^r-c^y 1 



EP 0 471 236 A1 



As the acyloxy lower alky I group, for example, there is an alkyl group having 1 to 6 carbon atoms which 
is substituted with a lower alkanoyl having 2 to 6 carbon atoms or benzoyloxyethyl such as acetoxyethyl, 
benzoyloxyethyl and the like. 

As the lower alkoxy-lower alkyl group, for example, there is an alkyl group having 1 to 6 carbon atoms 
5 which is substituted with an alkoxy group having 1 to 6 carbon atoms such as methoxyethyl, ethoxyethyl, 
propoxyethyi, butoxyethyl, methoxypropyl, methoxybutyl, ethoxypropyl, ethoxybutyl and the like. 

As the lower alkoxy group, for example, there is an alkoxy group having 1 to 6 carbon atoms such as 
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. 

As the halogeno lower alkoxy group, for example, there is an alkoxy group having 1 to 6 carbon atoms 
w which is substituted with 1 to 3 halogen atoms such as chloroethoxy, fluoroethoxy, difluoroethoxy, 
trifluoroethoxy, chloropropoxy, chlorobutoxy and the like. 

As the lower alkoxycarbonyl lower alkoxy group, for example, there is an alkoxy group having 1 to 6 
carbon atoms of which alkoxy moiety is substituted with an alkoxycarbonyl group having 1 to 6 carbon 
atoms such as methoxycarbonylmethoxy, ethoxycarbonylmethoxy, butoxycarbonylmethoxy, methoxycar- 
75 bonylpropoxy, ethoxycarbonylethoxy and the like. 

As the lower alkenyloxy group, for example, there is an alkenyloxy group having 2 to 6 carbon atoms 
such as vinyloxy, allyloxy, butenyloxy and the like. 

As the aralkyloxy group, for example, there is a phenyl lower alkyloxy group of which lower alkyl moiety 
has 1 to 6 carbon atoms such as benzyloxy, phenethyloxy, 3-phenylpropyloxy, a-methylphenethyloxy, a- 
20 methylbenzyloxy, a-ethylbenzyloxy, £-ethylphenethyloxy, 0-methylphenethyloxy and the like. 

As the lower alkoxy-lower alkoxy group, for example, there is an alkoxy group having 1 to 6 carbon 
atoms which is substituted with an alkoxy group having 1 to 6 carbon atoms such as ethoxymethoxy, 
methoxyethoxy, butoxyethoxy, ethoxypropoxy and the like. 

As the lower alkoxycarbonyl, for example, there is an alkoxycarbonyl group of which alkoxy moiety has 
25 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the 
like. 

As the N,N-di lower alkylcarbamoyl group, for example, there is a N,N-dialkylcarbamoyl group of which 
alkyl moiety has 1 to 6 carbon atoms such as N.N-dimethylcarbamoyl, N.N-diethylcarbamoyl, N,N- 
dipropylcarbamoyl, N,N-dibutylcarbamoyl, N-ethyl-N-methylcarbamoyl and the like and a N,N-di lower 
30 alkylcarbamoyl group of which alkyl moieties are bound together to form a 5 or 6 membered ring (e.g. N- 
pyrrolidinylcarbonyl, piperidinocarbonyl, etc.). 

As the N-lower alkylcarbamoyl group, for example, there is a N-alkylcarbamoyl group of which alkyl 
moiety has 1 to 6 carbon atoms such as N-methylcarbamoyl, N-ethyicarbamoyl, N-propylcarbamoyl, N- 
butylcarbamoyl and the like. 
35 Examples of halogen include chloro, fluoro, bromo and iodo. 

As the acyloxy group, for example, there is an alkanoyloxy group having 2 to 6 carbon atoms such as 
acetoxy, propanoyloxy, butylyloxy, pivaloyloxy and the like, and benzoyloxy group. 

As the lower alkylsulfonylamino group, for example, there is an alkylsulfonylamino group having 1 to 6 
carbon atoms such as methanesulfonylamino, ethanesulfonylamino and the like. 
40 As the acylamino group, for example, there is an alkanoylamino group having 1 to 6 carbon atoms such 
as acetamide, propanoylamino, butylylamino, pivaloylamino and the like and benzamide group. 

As the lower alkoxycarbonylamino group, for example, there is an alkoxycarbonylamino group of which 
alkoxy moiety has 1 to 6 carbon atoms such as methoxycarbonylamino, ethoxycarbonylamino, propoxycar- 
bonylamino, butoxycarbonylamino and the like. 
45 As the acyl group, for example, there is an alkanoyl group having 2 to 6 carbon atoms such as acetyl, 

propanoyl, butylyl, pivaloyl and the like and benzoyl group. 

As the lower alkylthio group, for example, there is an alkylthio group having 1 to 6 carbon atoms such 
as methylthio, ethylthio, propylthio, butylthio and the like. 

As the lower alkylsulfinyl group, for example, there is an alkylsulfinyl group having 1 to 6 carbon atoms 
so such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl and the like. 

As the lower alkylsulfonyl group, for example, there is an alkylsulfonyl group having 1 to 6 carbon 
atoms such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like. 

In -NR U R 15 , examples of the group wherein R u and R 15 together with the adjacent nitrogen atom are 
bound together to form a ring include a 3 to 8 membered monocyclic heterocyclic group such as 1- 
55 aziridinyl, 1-azetidinyl, piperidino, perhydro-1 -azepinyl, perhydro-1 -azocynyl, morpholino, thiomorpholino, 1- 
piperazinyl, 3-thiazolidinyl and the like; a condensed bicyclic or bridged bicyclic heterocyclic group such as 
1-indolyl, perhydro-1 -indoiyl, 2-isoindoIyl, perhydro-2-isoindolyl, 1 ,2,3,4-tetrahydro-1-quinolyl, 1,2,3,4- 
tetrahydro-2-isoquinolyl, perhydro-1 -quinolyl, perhydro-2-isoquinoly!, 3-azabicyclo[3.2.2.]non-3-yl and the 

8 



BNSDOCID: <E^ CW71236AV I > 



EP 0 471 236 A1 

like; a condensed tricyclic heterocyclic group such as 9-carbazolyl, 10-acridanyl, 



5 




I 

w 

10,1 1-dihydro-5H-5-dtbenz[b,f]azepinyl, 5,6,1 1 ,12-tetrahydro-5-dibenz[b,f]azocinyl, 1 ,2,3,4-tetrahydro-9-car- 
bazolyl, 1 0-phenoxadinyl, 10-phenothiadinyl and the like- 
As the substituent of the above heterocyclic group, for example, there are the same groups as those of 
;s -NR 10 R 11 . 

As the optionally protected amino group of R 1 and R 2 , for example, there are amino group, acylamino 
group and trimethylamino group, and examples of the acyl group include the same groups as those of R 11 . 

As the ring formed by connecting R* with R 5 , or R 6 with R 7 , or R 8 with R 9 , for example, there are 
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. 
20 As the ring formed by connecting R 4 or R 6 with R 8 or R 9 , respectively, for example, there are 

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. 

The compound of the formula (I) forms a salt, for example, an acid addtion salt with an inorganic acid 
such as hydrochloric acid, hydrobromic acid, sulfuric acid, phophoric acid or the like, or an organic acid 
such as acetic acid, oxalic acid, methanesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, 
25 lactic acid or the like. 

Examples of a solvent of the solvate include alcohols such as methanol, ethanol, propanol, isopropanot 
and the like; ketones such as acetone and the like; ethers such as tetrahydrofuran, dioxane and the like. 

The compound of the formula (I) may contain an assymetric carbon in the molecule. When two kinds of 
stereoisomers of Reconfiguration and S-configuration are present, not only the separated isomers, but also a 
30 mixture thereof are included in the scope of the present invention. 

Among the compounds represented by the formula (I), the compounds of the formula (I'): 



35 




' ) 



X-A-B 1 

40 

wherein X, A, R 1 and R ? are as defined above and B : is an amino group acylated by an acyl group derived 
from carboxylic acid having 2 or more carbon atoms, sulfonic acid, carbamic acid or thiocarbamic acid; the 
compounds of the formula (I"): 

45 



EP 0 471 236 A1 



5 




R 1 



(I 



i it 



) 



X-A-B* 



wherein X, A, R 1 and R 2 are as defined above and B 3 is a hydroxyl group acylated by an acyi group derived 
w from carboxylic acid or N-hydrocarbon substituted carbamic acid; and acid addition salts and solvates of 
these compounds have not been described heretofore in the prior art. Therefore, the present invention also 
provides these novel compounds. 

As the amino group acylated by an acyl group derived from carboxylic acid having 2 or more carbon 
atoms, sulfonic acid, carbamic acid or thiocarbamic acid, there is, for example, a group of the formula: 
75 -NR 10 R 11 [wherein R 10 ' is a hydrogen, or an optionally substituted alkyl, aralkyl or aryl group, or a group of 
the formula: -CO-R 12 , -S0 2 R 13 , -CO-NR 14 R 15 or -CS-N-R U R 15 , R 11 is a group of the formula: -CO-R 16 , 
-SO2R 17 , -CONR 14 R 15 or -CS-NR l4 R 15 (all other symbols are as defined above)]. R 10 ' is preferably 
hydrogen or, an optionally substituted alkyl, aralkyl or aryl group or, a group of the formula: -S0 2 R 13 , -CO- 
NR U R 15 or -CS-NR U R 15 . R 11 is preferably a group of the formula: -SO2R 17 , -CO-NR 14 R 15 or -CS-NR 1 *R 15 . 
20 Particularly, R 10 is hydrogen and R 11 is a group of the formula: -S0 2 R 13 (all the symbols are as defined 
above). 

Examples of the ring formed by connecting the nitrogen atom of the acylated amino group of B 2 with 
the carbon atom of A or R 3 include the above rings formed by connecting R 10 with R 3 , R\ R 6 or R 8 . 

As the hydroxyl group acylated by an acyl group derived from a carboxylic acid or N-hydrocarbon 
25 substituted carbamic acid, there is, for example, a group of the formula: -0-CO-NR 15 R 16 or -O-CO-R 19 - 
(wherein all the symbols are as defined above). 

B 3 is preferably a group of the formula: -O-CO-NHR 16 (wherein R 1S is as defined above). 
Among the compounds of the formula (I), those wherein X is S or O, B is (1) an amino group acylated 
by an acyl group derived from a sulfonic acid, a carbamic acid or thiocarbamic acid, (2) a hydroxyl group 
30 acylated with an acyl group derived from a carboxylic acid or a carbamic acid, or (3) a ring formed by 
connecting the nitrogen atom of the acylated amino group of B with a carbon atom of A or R 3 . As the group 
B, an amino group acylated by an acyl group derived from a sulfonic acid is particularly preferred. 

The starting materials or intermediates used for the production of the end products represented by the 
formula (I) are easily produced by the known processes or the per se known processes. 
35 lmidazo[1 ,2-a)pyridine derivatives (I) and the salts thereof of the present invention can be synthesized 

for example, as follows: 

(A) When X is S, O or NR 3 in the formula (I), a compound of the formula (II): 



wherein E is halogen such as chloro, bromo or iodo and the other substituents are as defined above, or a 
salt thereof reacts with a compound of the formula (111): 



40 




(ID 



45 



H-X 1 -A-B 



(III) 



50 



wherein X 1 is S, O or NR 3 and the other symbols are as defined above, to give the compound (I). 
(B) When X is S or O in the formula (I), a compound of the formula (IV): 



55 



10 



3NSDOCID <EP 0471236A1 I > 



EP 0 471 236 A1 



5 




(IV) 



wherein X 2 is S or O and the other symbols are as defined above, or a salt thereof reacts with a 
compound of the formula: 

10 

E^A-B (V) 

wherein E 1 is a leaving group such as halogen (i.e. chloro, bromo, iodo, etc.), toluenesulfonyl group or 
methanesulfonyl group and the other symbols are as defined above, to give the compound (I). 
75 (C) When B is -NR 10 -CO-NR 14 FT 5 , -NFP°-CS-NR 14 R 15 or -0-CO-NR 14 R 15 in the formula (I), a compound 
of the formula (VI): 



20 




(VI) 



25 

wherein B 1 is -O- or -NR 10 - and the other symbols are as defined above, or a salt thereof reacts with a 
compound of the formula: 

Q 1 -NR U R 15 (VII) 

30 

wherein Q 1 is PhO-CO, G-CO- or G-CS- (wherein Ph is a phenyl group and G is halogen such as chloro, 
etc.) and the other symbols are as defined above, or a salt thereof, to give the compound (I). 
(D) When B is -NR^-CO-NR^R 15 , -NR 10 -CS-NR 14 R 15 or -0-CO-NR u R 15 in the formula (I), a compound 
of the formula (VIII): 

35 



4D 




(VIII) 



X-A-Q 2 

wherein Q 2 is OCN-, SCN-, PhO-CO-O, G-CO-NR 10 - or G-CO-O-and the other symbols are as defined 
45 above, or a salt thereof reacts with a compound of the formula (IX): 



HNR U R' 5 (IX) 



EP 0 471 236 A1 



5 



70 



25 



30 



35 



40 



45 



SO 



wherein ail the symbols are as defined above, or a salt thereof reacts with an oxidizing agent, to give the 
compound (I). 

(F) When R 2 is halogen such as chloro, bromo, iodo and the like in the formula (I), a compound of the 
formula (lb): 




(lb) 
X- A-B 



wherein all the symbols are as defined above, or a salt thereof reacts with a halogenating agent, to give 
75 the compound (I). 

(G) When R 2 is nitro in the formula (I), a compound of the formula (lb), or a salt thereof is nitrated to 
obtain the compound (I). 

(H) When R 2 is a nitroso group in the formula (I), a compound of the formula (lb) or a salt thereof is 
nitrosated to give the compound (I). 

20 (I) When R 2 is CH 2 R 2a (wherein R 2a is a lower dialkylamino group or a cyclic amino group) in the formula 

(I) , the compound (I) is prepared by, for example, the following reaction: 



HCH(\R aa -H 
(lb) > (I) 



(J) a compound of the formula (X): 



B-A-X 




(X) 



wherein all the symbols are as defined above, or a salt thereof reacts with a compound of the formula 
(XI): 

R 1 -CO-CHE-R 2 (XI) 

wherein the symbols are as defined above, to give the compound (I). 

(K) When R 11 is COR 16 in the formula (I), a compound of the formula (XII): 




(XII) 



wherein the symbols are as defined above, or a salt thereof reacts with a compound of the formula (XIII): 

55 G 1 -CO(0) q -R 16 (XIII) 

wherein G 1 is halogen such as chloro, etc. or R 16 (0) g -CO-0-(wherein q is 0 or 1) and the other symbols 
are as defined above, to give the compound (I). 

12 

BNSDOCID <EP 0471236A •!_!_> 



EP 0 471 236 A1 



(L) The compound (XII) or a salt thereof is reacted with a compound of the formula (XIV): 
G 2 -S0 2 R' 7 (XIV) 

5 wherein G 2 is halogen such as chloro, etc. or R l7 S0 2 O and the other symbols are as defined above, to 
give the compound (I). 

(M) When R 2 is an amino group in the formula (I), reduction of a compound of the formula (I) wherein R 2 
is nitro or nitroso, or a salt thereof gives the compound (1) wherein R 2 is an amino group. In the case of a 
protected amino group, the amino group is further acylated or tritylated. 
io In the above processes A to M, a compound which can form a salt may be used in the salt form, and 
examples of such a salt include those as described in the above compound (1). In the following explanation 
of the processes A to M, a salt of each compound may be included. 

The reaction of the compound (II) with the compound (III) in the process A can be conducted at -10* C 
to +200*C in a solvent in the presence of a basic compound such as sodium hydroxide, potassium 
75 hydroxide, sodium hydride, potassium carbonate or the like by using 1 equivalent to extremely excessive 
amount (1 to 10 equivalents) of the compound (III) per t equivalent of the compound (II). Examples of the 
solvent to be used include water; lower alcohols such as methanol, ethanol, propanol and the like; ketones 
such as acetone, methyl ethyl ketone and the like; ethers such as tetrahydrofuran and the like; and non- 
aprotic polar solvents such as N.N-dimethylformamide, diethylsulfoxide and the like. The reaction time is 
20 normally 1 hour to 2 days, preferably 1 to 8 hours. 

The reaction of the compound (IV) with the compound (V) in the process B is conducted under 
conditions similar to those of the reaction of the compound (II) with the compound (III) in the process A. 

The reaction of the compound (VI) with the compound (VII) in the process C is conducted at -10* C to 
+ 150*C in the absence or presence of a solvent (e.g. ether, toluene, benzene, chloroform, dich- 
25 loromethane, dioxane, tetrahydrofuran, dimethylformamide, etc.). In order to promote the reaction, a tertiary 
amine (e.g. triethylamine, pyridine, diethylaminopyridine, N-methylpiperidine, etc.) can be added. The 
compound (VII) is used in an amount of 1 to 10 equivalents per 1 equivalent of the compound (VI). 

The reaction of the compound (VIII) with the compound (IX) in the process D is conducted under 
conditions similar to those of the raction of the compound (VI) with the compound (VIII) in the process C. 
30 Further, when Q 2 is -NCO-, boron trifluoride-ethyl ether (BF 3 *Et 2 0) can be added. The reaction time is 
normally 0.5 to 24 hours, preferably 0.5 to 6 hours. 

The oxidation of the compound (la) in the process E can be conducted at -30 to +100*C in the 
presence of a solvent by using 1 equivalent to extremely excess amount (1 to 10 equivalents) of an 
oxidizing agent per 1 equivalent of the compound (lb). Examples of the solvent to be used include water, 
35 methanol, ethanol, dichloromethane, chloroform and the like. Examples of the oxidizing agent include m- 
chloroperbenzoic acid, sodium methaperiodate, hydrogen peroxide and the like. The reaction time is 
normally 0.5 hours to 2 days, preferably 0.5 to 12 hours. 

The reaction of the compound (lb) with a halogenating agent in the process F can be conducted at -20 
to + 150* C in the absence or presence of a solvent by using 1 equivalent to extremely excess amount (1 to 
40 10 equivalents) of the halogenating agent per 1 equivalent of the compound (lb). Examples of the solvent to 
be used include halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, carbon 
tetrachloride and the like; acetic acid; propionic acid; and the like. Examples of the halogenating agent 
include a halogen molecule such as chlorine, bromine and the like; N-halogenosuccinimide such as N- 
chlorosuccinimide, N-bromosuccinimide and the like. Further, a radical reaction initiator such as benzoyl 
45 peroxide or the like can be added in the above reaction. The reaction time is normally 0.5 to 2 hours, 
preferably 1 to 12 hours. 

The nitration of the compound (lb) in the process (G) can be conducted at -20 to +100 C in the 

pn ^ enre or prosenre a solvent hv usinn 1 equivalent to extremelv excess amount M to 10 equivalents of 



cinhydnue ano nur l auo arc -no nut; i nu reaction ti^'a; »t r^rmauy u ^ to nours. pre\*rauy o t> o 
hours. 

The nitrosation of the compound (lb) in the process H can be conducted at -20 to +100 C in the 

-.r on--r.n rr rrr.ff.-v-f. < 1 c-'-/r»rt rv 's''-^; 1 *T'0 'O r,r *'i • r ' * x "' r ' ^ 0 ' V r ' < ' e "~ S anr.fv.r.t [ 1 ?0 1 r r-oj iv.' f ' r 'v 



EP 0 471 236 A1 



Examples of the nitrosating agent inciude potassium nitrite, sodium nitrite and the like. The reaction is 
conducted in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid 
or the like. The reaction time is normally 0.5 to 24 hours, preferably 0.5 to 6 hours. 

Mannich reaction of the compound (lb) with a lower dialkylamine or a cyclic amine and formalin in the 

5 process I can be conducted at -20 to +100*C in the presence of a solvent by using 1 equivalent to 
extremely excess amount (1 to 10 equivalents) of a Mannich reagent per 1 equivalent of the compound (lb). 
Examples of the solvent to be used include water; lower alcohols such as methanol, ethanol, propanol, 
isopropanol and the like; lower fatty acids such as acetic acid, propionic acid and the like. The reaction time 
is normally 30 minutes to 1 day, preferably 1 to 12 hours. 

to The reaction of the compound (X) with the compound (X!) in the process J can be conducted at 0 to 
+ 200* C in the absence or presence of a solvent by using 1 equivalent to extremely excess amount (1 to 
10 equivalents) of the compound (XI) per 1 equivalent of the compound (X). Examples of the solvent to be 
used include water; lower alcohols such as methanol, ethanol, propanol and the like; ethers such as 
tetrahydrofuran, dimethoxyethane, dioxane and the like; nitriles such as acetonitrile, propionitrile and the 

75 like; aprotic polar solvents such as N.N-dimethylformamide, dimethylsulfoxide and the like. Further, in the 
above reaction, an inorganic base such as potassium carbonate, sodium bicarbonate or the like, or an 
organic base such as triethylamine, pyridine, dimethylanilin or the like can be added as an acid-trapping 
agent. The reaction time is normally 10 minutes to 7 days, preferably 1 hour to 2 days. 

The reaction of the compound (XII) with the compound (XIII) in the process K can be conducted at -30 

20 to +200*C in a solvent in the absence or presence of an inorganic base such as potassium carbonate, 
sodium bicarbonate or the like or an organic base such as triethylamine, pyridine, dimethylanilin, 1,4- 
diazabicyclo[2.2.2]octane (DABCO) or the like by using 1 equivalent to extremely excess amount (1 to 10 
equivalents) of the compound (XIII) per 1 equivalent of the compound (XII). Examples of the solvent to be 
used include halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the 

25 like; ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane and the like; esters such as methyl 
acetate, ethyl acetate and the like; aprotic polar solvents such as N.N-dimethylformamide, dimethylsulfoxide 
and the like. The reaction time is normally 10 minutes to 24 hours, preferably 0.5 to 6 hours. 

The reaction of the compound (XII) with the compound (XIV) in the process L is conducted under 
conditions similar to those of the reaction of the compound (XII) with the compound (XIII) in the process K. 

30 The reduction of the compound (I) wherein R 2 is nitro group or nitroso group in the process M can be 

conducted at -20 to +200*C in the presence of a solvent by using 1 equivalent to extremely excess 
amount (1 to 10 equivalents) of a reducing agent per 1 equivalent of the compound (I). Examples of the 
solvent to be used include water, methanol, ethanol, propanol, isopropanol, acetic acid and the like. 
Examples of the reducing agent include a mixture of iron and hydrochloric acid or a mixture of zinc and 

35 acetic acid. Further, the reaction can be conducted at -20 to + 20 * C in the presence of a solvent under 
normal hydrogen pressure by using a hydrogenating catalyst such as palladium black, palladium carbon, 
raney nickel or the like. Examples of the solvent to be used include water, methanol, ethanol, propanol, 
isopropanol, acetic acid and the like. The reaction time is normally 10 minutes to 24 hours, preferably 0.5 to 
6 hours. When the protected amino group is -NH-CO-NR u R 15 or -NH-CS-NR 14 R 15 , it can be obtained by 

40 reacting the compound of the formula (I) wherein R 2 is an amino group with the compound (VII). This 
reaction is conducted under conditions similar to those of the reaction of the compound (VI) with the 
compound (VII) in the process C. When the protected amino group is tritylamino group, it can be obtained 
by reacting the compound of the formula (I) wherein R 2 is amino group with trityl chloride. This reaction is a 
known reaction and it can be conducted according to known conditions. 

45 The compound (II) can be obtained, for example, by the following process. 



50 




(XI) 

> <n) 



(XV) 

The reaction of the compound (XV) with the compound (XI) is conducted under conditions similar to 
55 those of the reaction of the compound (X) with the compound (XI). 

The compound (IV) can be obtained, for example, by the following process. 



14 



BNSDOCID: <EP___ 0471236A1 



EP 0 471 236 A1 



Cn) 



YH 
(X VI) 



> (IV) 



wherein Y is NaS-, KS-, NaO- or KO-. 

The reaction of the compound (II) with the compound (XVI) can be conducted at 0 to +250*C in the 
presence of a solvent by using 1 equivalent to extremely excess amount of the compound (XVI) per 1 
equivalent of the compound (II). Examples of the solvent to be used include water; lower alcohols such as 
methanol, ethanol, propanol and the like; ethers such as tetrahydrofuran, dimethoxyethane, dioxane and the 
like; aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide and the like. 

The compound (VI) can be obtained, for example, by the following processes, 
(i) When X is S or O, 



(IV) 



E l -A-B l H 
(XVI) 



> (VI) 



wherein the symbols are as defined above; 
(ii) When X is S. O or NR 3 , 



(n) 



HX-A-B'H 
(XVffl) 



> (VI) 



wherein the symbols are as defined above; 
(iii) When X is S or O and B 1 is NR 10 , 




I R 2 

X-A-B l T 
(X X) 



removal of 
protecting group 



> (VI) 



wherein T is an amino protecting group such as benzyloxycarbonyi, tert-butoxycarbonyl, trifluoroacetyl, 



EP 0 471 236 A1 



70 



(IV) 



E'-A-OH 
(X XI) 



conversion of OH 

1) into E 1 

2) R 10 NH 




(VI) 



75 



wherein the symbols are as defined above; 
(vi) When X is S, O or NR 3 and B 1 is NR 10 , 



20 



(n) 



HX l -A-0H 

(x x m) 



-> (x x n ) 



25 



conversion of OH 

1 ) into E 1 

2) R 10 NH ^ 



(VI) 



30 



35 



40 



45 



50 



wherein the symbols are as defined above. 

The reaction of the compound (IV) with the compound (XVII) in the process (i) is conducted under 
conditions similar to those of the reaction of the compound (IV) with the compound (V) in the process B. 

The reaction of the compound (II) with the compound (XVIII) in the process (ii) is conducted under 
conditions similar to those of the reaction of the compound (II) with the compound (III) in the process A. 

The reaction of the compound (IV) with the compound (XIX) in the process (iii) is conducted under 
conditions similar to those of the reaction of the compound (IV) with the compound (V) in the process B. 

The reaction of the compound (XX) with the oxidizing agent in the process (iv) is conducted under 
conditions similar to those of the reaction of the compound (la) with an oxidizing agent. 

The reaction of the compound (IV) with the compound (XXI) in the process (v) is conducted under 
conditions similar to those of the reaction of the compound (IV) with the compound (V) in the process B. 

The reaction of the compound (II) with the compound (XXIII) in the process (vi) is conducted under 
conditions similar to those of the reaction of the compound (II) with the compound (III) in the process A. 

The conversion of the hydroxyl group of the compound (XXII) in the processes (v) and (vi) into E 1 is 
conducted by, when E 1 is halogen, reacting the compound (XXII) with a halogenating agent such as a 
phophorous halide (e.g., phosphorous trichloride, phosphorous oxychloride, phosphorous pentachloride, 
phosphorous tribromide, etc.), red phosphorous and halogen, or thionyl chloride and the like. When E 1 is 
toluenesulfonyl group or methanesulfonyloxy group, it can be obtained by the reaction of the compound 
(XXII) with toluenesulfonyl chloride or methanesulfonyl chloride. The reaction with R 10 NH which follows the 
above reaction is conducted at 0 to 200* C in the absence of any solvent or in a suitable solvent. 

All of those reactions are known and they can be conducted according to known conditions. 

The compound (VIII) can be obtianed, for example, by the following processes, 
(i) When Q 2 is OCN-, 



55 



16 

BNSDOCID cEP..._0471236A1_l_> 



EP 0 471 236 A1 




1) Phosgen e 

2) -HCfl 



(Vffl) 



wherein the symbols are as defined above; 
(ii) When Q 2 is OCN-, 




R 2 
X-A-E 

(XXV) 



AgOCN 



wherein the symbols are as defined above; 
(iii) When Q 2 is SCN-, 



1) NaOH^CS, ^ , 
(XXIV) > (VI) 

2) CCC0 2 Et 

3) A 



(iv) When CP is SCN-, 



(XXV) 



Y'SCN 
(X X VI) 



-> (Vrj) 



wherein Y' is Na or K; 

(v) When Q 2 is PhO-CO-O, 



(xn) 



CfiCCPh 



^ (Vffl) 



(vi) When Q- is G-CO-NR' r \ 



EP 0 471 236 A1 



P hosgene ^ 

Cn) > (vni) 

5 



(vii) When Q 2 is G-CO-O-, 

w 

Phosgene 

(xi) - > (vm) 

75 



Namely, (i) the compound (XXIV) Is reacted with phosgene, and then the reaction product is heated for 
20 dehydrochlorination. 

(ii) The compound (XXV) is reacted with silver cyanate. 

(iii) The compound (XXIV) is reacted with CS2 and further with chlorocarbonate, and then the reaction 
product is heated. 

(iv) The compound (XXV) is reacted with the compound (XXVI). 
25 (v) The compound (XXM) is reacted with phenyl chlorocarbonate. 

(vi) The compound (XII) is reacted with phosgene. 

(vii) The compound (XXII) is reacted with phosgene. 

All the reactions are known and they can be conducted according to known conditions. 
All the reactions for removing the above protecting groups are known and they can be conducted 
30 according to known conditions. 

For example, benzyloxycarbonyl group or benzyl group as the amino protecting group can be removed 
by a catalytic reduction (reaction temperature: room temperature to + 100* C) in a solvent (e.g., alcohol, 
acetic acid, water, tetrahydrofuran and a mixed solvent thereof, etc.) in the presence of a catalyst (e.g., 
palladium on carbon, platinum oxide, etc.). 
35 In the case of trityl group or tert-butoxycarbonyl group, it can be removed at 0 to +150* C in a solvent 

(e.g., water, alcohol, tetrahydrofuran, dioxane, etc.) in the presence of an acid (e.g., mineral acids such as 
hydrochloric acid, phophoric acid, sulfuric acid and the like; organic acids such as toluenesulfonic acid, 
methanesulfonic acid, acetic acid and the like). Trifluoroacetyl group can be readily removed by treating 
with an alkali (e.g., sodium hydroxide, sodium bicarbonate solution, etc.) 
40 Phthalamide group can be removed by reacting with hydrazine hydrate in a solvent (e.g., methanol, 

ethanol, etc.). 

The starting compounds can be removed from the desired product (I) obtained by the above processes 
or a salt thereof by the following conventional separation means. Or, a reaction mixture per se may be used 
as a starting material for the next step without purification. 
45 The isolation and purification of the compound (I) or a salt thereof from the reaction mixture is 

conducted according to conventional separation means (e.g., extraction, concentration, filtration, recrystal- 
lization, column chromatography, thin layer chromatography, etc.). 

The compounds (I) of the present invention or salts thereof have calmodulin inhibitory activity and are 
useful as safe medicines for various diseases of mammal (e.g., human, dog, cat, etc.) such as hypertension, 
so ischemic diseases (e.g., angina, cardiac infarction, arrhythmia, renal failure, etc.), arteriosclerosis, vascular 
jerk after subarachnoid hemorrhage and inflammatory diseases (e.g., nephritis, asthma, hepatitis, etc.) and 
the like. 

When the compound (I) of the present invention or a salt thereof is used as the above medicines, it can 
be admixed with a pharmaceutical^ acceptable carrier, excipient, diluent and administered orally or 
55 parenterally in a dosage form such as powder, granules, tablets, capsules, injection and the like. A dosage 
varies depending upon a particular administration route, conditions to be treated, age and weight of the 
patient and the like. For example, when it is orally administered to an adult patient, the dosage may be 0.2 
to 50 mg/kg/day, preferably 0.5 to 30 mg/kg/day, more preferably 1 to 20 mg/kg/day and it can be 

18 

BNSDOCID; <EP 0471 236A1 J_ --> 



EP 0 471 236 A1 



administered once to several times in a day. 

As described hereinabove, the compounds (I) of the present invention and salts thereof have excellent 
calmodulin inhibitory activities and are useful as hypotensors and medicines for treating ischemic diseases, 
antiarteriosclerotic agents, medicines for treating vascular jerk after subarachnoid hemorrhage, anti-inflam- 
5 matory agents and the like in human and mammal. 

The following Reference Examples, Examples, Preparations and Experiments further illustrate the 
present invention in detail but are not to be construed to limit the scope thereof. In Examples, room 
temperature means 15 to 30* C. 

w Reference Example 1 



(1) Synthesis of 2-ethoxycarbonyl-5-chloroimidazo[1 ,2-a] pyridine 

A solution of 2-amino-6-chloropyridine (6.43 g, 50 mmoles) and ethyl bromopyruvate (9.75 g, 50 
75 mmoles) in ethanol (150 ml) was heated at reflux for 4 hours. After the solvent was removed, chloroform 
was added to the residue, which was washed in turn with saturated sodium bicarbonate and saturated 
saline, and then dried over anhydrous magnesium sulfate. After the solvent was concentrated, n-hexane was 
added to the mixture. Then, the crystals precipitated were filtered off and washed with n-hexane to obtain 
7.60 g of the desired product (67.6%, pale yellow crystals). 
20 Melting point: 143-145° C 





Elemental analysis for C10H9N2O2CI, 




Calcd.: 


C, 53.47; 


H, 4.04; 


N, 12.47 


25 


Found : 


C, 53.45; 


H, 3.99; 


N, 12.59 



NMR (90MHz, CDCI3) 5:1.42 (3H, t, J = 7Hz), 4.46 (2H, q, J = 7Hz), 6.95 (1H, dd, J = 7, 1Hz), 7.24 (1H, dd, 
J = 7Hz), 7.67 (1 H, d, J = 9Hz), 8.36 (1 H, s) 

According to the same manner as that described in Reference Example 1 (1), the following compounds 
were obtained. 

(2) 5-Chloro-2-methylimidazo[1 ,2-a]pyridine 

NMR (90MHz, CDCI3) 5: 2.47 (3H, s), 6.79 (1H, d, J = 7Hz), 7.08 (1H, dd, J = 9, 7Hz), 7.47 (1H, d, J = 9Hz), 
7.51 (1H, s) 

(3) 3-Ethoxycarbony!-5-chloro-2-methyhmidazo[1 ,2-a]pyridine 

NMR (90MHz, CDCI 3 ) 5:1 .40 (3H, t, J = 7Hz). 2.60 (3H, s), 4.43 (2H, q, J = 7Hz), 6.94 (1 H, dd, J = 1 Hz), 7.26 
(1H. dd, J = 9, 7Hz), 7.54 (1H, dd, J = 9, 1 Hz) 

(4) 2-Ethoxycarbonylmethyl-5-chloroimidazo[1 ,2-a]pyridine 

NMR (90MHz, CDCI 3 ) 5: 1.28 (3H, t, J=7Hz), 3.87 (2H t s), 4.21 (2H, q, J = 7Hz), 6.83 (1H, dd, J = 7, 1 Hz), 
7.12 (1H, dd, J = 9, 7Hz), 7.52 (1H, dd, J = 9, 1Hz), 7.78 (1H, s) 

Reference Example 2 



minutes. 5-chlcro-2-methyiimidazo[ 1 ,2-a]pyndme (3.33 g, 20 mmcies) was added to the mixture, followed by 
heating at reflux for 3 hours. After the solvent was distilled off, chloroform was added to the residue which 
was washed with iN-NaOH and dried over anhydrous potassium carbonate. After the solvent was distilled 



EP 0 471 236 A1 



According to the same manner as that described in Reference Example 2 (1), the following compounds 
were obtained. 

(2) 5"[2-(Amino)ethylthio]-2-ethoxycarbonylimidazo[1 ( 2-a]pyridine 





Elemental analysis for C 12 Hi5N 3 O2S*0.3H 2 O ( 




Calcd.: 


C, 53.24; 


H, 5.81; 


N, 15.52 


70 


Found : 


C, 53.43; 


H, 5.61; 


N, 15.54 



NMR (90MHz, CDCb) 6: 1.44 (3H, t, J = 7Hz), 1.52 (2H, br), 2.83-3.19 (4H, m), 4.46 (2H, q, J=7Hz), 7.00 
(1 H, dd, J = 7, 1 Hz), 7.20 (1 H, dd, J = 9, 7Hz). 7.64 (1 H, d, J = 9Hz), 8.49 (1 H, s) 

(3) 5-[2-(Amino)ethylthio]-3-ethoxycarbonyl-2-nnethylimidazo[1,2-a]pyridine 

NMR (90MHz, CDCl 3 ) 5: 1.40 (3H, t, J = 7Hz), 1.47 (2H, br), 2.61 (3H, s), 2.81 (2H, m), 3.04 (2H, m), 4.43 
(2H, q, J = 7Hz), 7.02 (1 H, dd, J = 7, 1 Hz), 7.30 (1 H, dd, J = 9, 7Hz), 7.48 (1 H, dd, J = 9, 1 Hz) 

(4) 5-[2-(Amino)ethylthio]-2-ethoxycarbony!methylimidazo[1,2-a]pyridine 

NMR (90MHz, CDCI3) 6: 1.29 (3H, t, J = 7Hz), 1.60 (2H, s), 2.80-3.20 (4H, m), 3.90 (2H, s), 4.21 (2H, q, 
J = 7Hz), 6.90 (1H, dd, J = 7, 1Hz), 7.11 (1H, dd, J = 9. 1Hz), 7.51 (1H, d, J = 9Hz), 7.89 (1H, s) 

(5) 5-[(4-Piperidyl)thio]imidazo[1 ,2-a]pyridine 

NMR (200MHz, CDCI3) 5:1.62 (2H, m), 1.93 (2H, m), 2.07 (1H, br), 2.64 (2H, m), 3.12 (2H, m), 3.33 (1H, m), 
7.02 (1H, d, J = 7Hz), 7.15 (1H, dd, J = 9, 7Hz), 7.62 (1H, d, J = 9Hz), 7.69 (1H, s), 7.96 (1H, s) 

Reference Example 3 



(1) Synthesis of 5-[4-(amino)butoxy]imidazo[1 ,2-a]pyridine 

To a suspension of 60% sodium hydride (oily; 1.32 g, 33 mmloes) in DMF (60 ml) was added a solution 
of 5-chloroimidazo[1,2-a]pyridine (4.59 g, 30.1 mmoles) and 4-aminobutanol (2.68 g, 30.1 mmoles) in DMF 
(60 ml) at room temperature with stirring and the mixture was stirred at the same temperature for 5 hours. 
Tert-butyl dicarbonate (9.83 g, 45 mmoles) was added to the reaction solution, which was stirred at room 
temperature for 13 hours. After the solvent was distilled off, water was added to the residue, which was 
extracted with ether twice, washed with water and dried over anhydrous magnesium sulfate, and then the 
solvent was distilled off. The residue was dissolved in methanol (20 ml), followed by the addition of cone, 
hydrochloric acid (20 ml) and stirring at room temperature for 1 hour. After the solvent was distilled off, 
chloroform was added to the residue, which was washed with 3N NaOH. After drying over anhydrous 
potassium carbonate, the solvent was distilled off. The residue was purified by column chromatography 
(eluent: methanol/chloroform = 1:5) to obtain 2.53 g of the desired product (40.9%, light brown oily 
product). 

NMR (200MHz, CDCI3) 5: 1.71 (2H, m), 1.96 (2H, br), 1.97 (2H, m), 2.83 (2H, m), 4.27 (2H, m), 6.03 (1H, d, 
J = 7.2Hz), 7.17 (1H, dd, J = 9, 7.2Hz), 7.27 (1H, d, J=9Hz), 7.59 (1H, d, J = 1.4Hz), 7.66 (1H, s) 

According to the same manner as that described in Reference Example 3 (1), the following compounds 
were obtained. 

(2) 5-[5-(Amino)pentyloxy]imidazo[1 ,2-a]pyridine 

NMR (200MHz, CDCI 3 ) 5: 1.58 (4H, m), 1.66 (2H, br), 1.96 (2H, m), 2.77 (2H, m), 4.25 (2H, t, J = 6, 4Hz), 
6.02 (1H, d, J = 7Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.27 (1H, d, J = 9Hz), 7.59 (1H; d, J = 1.4Hz), 7.66 (1H, s) 

(3) 5-[6-(Amino)hexyIoxy)imidazo[1 ,2-a)pyridine 

NMR (200MHz, CDCI3) 5: 1.34*1.70 (8H, s), 1.93 (2H, m), 2.73 (2H, m), 4.23 (2H, t, J = 6, 4Hz), 6.02 (1H, dd, 

20 

BNSDOCID. <EP__0471236A1_I_> 



EP 0 471 236 A1 



J = 7, 1Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.26 (1H, m), 7.59 (1H, d, J = 1.2Hz), 7.65 (1H, m) 

(4) 5-[2-[1 -(Amino)propoxy])imidazo[1 ,2-a]pyridine 

5 NMR (200HMz, CDCI 3 ) 5: 1.44 (3H, d, J = 6.2Hz), 1.75 (2H, br), 2.96-3.15 (2H, m), 4.63 (1H, m), 6.10 (1H, d, 
J = 7Hz), 7.17 (1H, dd, J = 9, 7Hz), 7.27 (1H, d, J = 9Hz), 7.59 (1H, d, J = 1.4Hz), 7.66 (1H, m) 

(5) 5-[2-(Amino)-1-(pheny!)ethoxy]imidazo[1 ( 2-a]pyridine 

NMR (200MHz, CDCI 3 ) 5: 1.75 (2H, br), 3.19 (1H, dd, J =14, 4.2Hz). 3.35 (1H, dd, J = 14, 7.4Hz), 5.38 (1H, 
70 dd, J = 7.4, 4.2Hz), 5.89 (1H, d, J = 7Hz), 701 (1H, dd, J = 9, 7Hz), 7.22 (1H, d, J=9Hz), 7.37 (5H, m), 7.64 
(1H, d, J = 1.2Hz), 7.82 (1H, s) 

(6) 5-[(4-Piperidinyl)oxy]imidazo[1 ,2-a]pyridine 

75 NMR (200MHz, CDCh) 5: 1.76 (1H, br), 1.87 (2H, m), 2.12 (2H, m), 2.82 (2H, m), 3.18 (2H, m), 4.67 (1H, m), 
6.06 (1H, d, J = 7.2Hz), 7.17 (1H, dd, J = 9, 7.2Hz), 7.27 (1H, d, J = 9Hz), 7.60 (1H, d, J = 1Hz), 7.69 (1H, s) 

Reference Example 4 

20 Synthesis of 5-[2-(phenoxycarbony!oxy)ethylthio]imidazo[1 ,2-a]pyridine 

To a solution of 5-[2-(hydroxy)ethylthio]imidazo[1 ,2-a]pyridine (5.83 g, 30 mmoles) and pyridine (4.36 
ml, 60 mmoles) in methylene chloride (120 ml) was added phenyl chloroformate (7.53 ml, 60 mmoles) with 
stirring under ice-cooling and the mixture was stirred under ice-cooling for 30 minutes. The reaction solution 
25 was washed in turn with an aqueous 5% sodium bicarbonate solution and saturated saline and dried over 
anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column 
chromatography (eluent: ethyl acetate) to obtain 8.61 g of the desired product (91.3%, oily product). 
NMR (200MHz, CDCI3) 5: 3.30 (2H, t, J = 6.6Hz), 4.42 (2H, t, J = 6.6Hz), 7.06-7.45 (8H, m), 7.69 (1H, d, 
j = ^ .4Hz) ? 7.73 (1 H, d, J = 1 .4Hz), 7.92 (1 H, m) 

30 

Reference Example 5 



Synthesis of 5-[2-(methylsulfonyloxy)ethylthio]imidazo[1 ,2-a]pyridine 

35 To a solution of 5-[2-(hydroxy)ethylthio]imidazo[1 ,2-ajpyridine (9.71 g, 50 mmoles) and triethylamine 
(10.5 ml, 75.3 mmoles) in methylene chloride (300 ml) was added methanesulfonyl chloride (4.26 ml, 55 
mmoles) with stirring under ice-cooling and the mixture was stirred under ice-cooling for 2 hours. The 
reaction solution was washed in turn with an aqueous saturated sodium bicarbonate solution and saturated 
saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled oft to obtain 13.6 g of 

40 the desired product (quantitative, brown oily product). 

NMR (200MHz, CDCI3) 5: 2.97 (3H, s), 3.28 (2H, t, J = 6.4Hz), 4.35 (2H, t, J = 6.4Hz), 7.08 (1H, dd, J = 7, 
1.2Hz), 7.18 (1H, dd, J = 8.8, 7Hz), 7.64 (1H, m), 7.73 (1H, d, J = 1 .4Hz), 7.91 (1H, m) 

Reference Example 6 

45 

(1) Synthesis of 5-[2-(methylamino)ethylthio]imidazo[1 ,2-a]pyridine 

A solution of 5-[2-(methylsulfonyloxy)ethylthio]imidazo[1 ,2-a]pyridine (2 18 q. 8 mmoles), triethylamine 



{47.1%, light brown oily product). 

NMR (200MHz, CDCI3) 5: 2.31 (1H, br), 2.88 (2H. 1, J = 6 4Hz), 3.16 (2H, t, J = 6 4Hz), 6.94 (1H, dd. J = 
1HzV 7 15 (1H dd. J = 9. 7Hz), 7.58 MH, dd. J = 9 1 Hz). 7 69 (1 d. J = 1 ?HrV 7 86 MH, r 



EP 0 471 236 A1 



(2) 5-[2-(Ethy!amino)ethylthio]imidazo[1 ,2-a]pyridine 

NMR (200MHz, CDCI 3 ) 5: 1.11 (3H, t, J = 7Hz), 1.88 (1 H, br), 2.70 (2H, m), 2.90 (2H, t, J = 6.2Hz), 3.15 (2H, 
t, J = 6.2Hz), 6.94 (1H, dd, J = 7, 1Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.59 (1H, dd, J = 9, 1Hz), 7.70 (1H, d, 
5 J = 1.2Hz), 7.87 (1H, s) 

IR (KBr) cm" 1 : 3280, 3105, 2965, 2930, 2890, 2820, 1655, 1620, 1530, 1490 

Reference Example 7 



io (1) Synthesis of 5-[3-(amino)porpoxy]imidazo[1 ,2-a]pyridine 

To a solution of 5-[3-(ter1-butoxycarbonylamino)propoxy]imidazo[1 ,2-a]pyridine in methanol (10 ml) was 
added concentrated hydrochloric acid (5 ml) and the mixture was stirred at room temperature for 1 hour. 
After the solvent was distilled off, chloroform (30 ml) and 3N-NaOH (10 ml) were added to the residue which 
75 was extracted with chloroform and dried over anhydrous potassium carbonate. Then, the solvent was 
distilled off to obtain 687 mg of the desired product (78.7%, pale yellow oily product). 

NMR (200MHz, CDCI 3 ) 5: 1.51 (2H, br), 2.07 (2H, m), 3.00 (2H, t, J = 6.8Hz), 4.35 (2H, t, J = 6.2Hz), 6.06 (2H, 
d, J = 7Hz), 7.17 (1H, dd, J =9, 7Hz), 7.28 (1H, d, J=9Hz), 7.59 (1H, d, J = 1.4Hz), 7.65 (1H, s) 

According to the same manner as that described in Reference Example 7 (1), the following compounds 
20 were obtained. 

(2) 5-[2-(Amino)ethoxy]imidazo[1 ,2-a]pyridine 

NMR (200MHz, CDCI3) 6: 1.66 (2H, br), 3.25 (2H, t, J = 5.2Hz), 4.28 (2H, t, J = 5.2Hz), 6.06 (2H, d, J = 7Hz), 
25 7.17 (1H, dd, J = 9, 7Hz), 7.29 (1H, d, J = 9Hz), 7.61 (1H, d, J = 1 Hz), 7.68 (1H, s) 

(3) 5-[2-(Amino)ethylamino]imidazo[1 ,2-a]pyridine 

NMR (90MHz, CDCI 3 ) 5: 1.70 (2H, br), 3.07 (2H, m), 3.29 (2H, m), 5.17 (1H, br), 5.88 (1H, dd, J = 6, 2.5Hz), 
30 7.02-7.30 (2H, m), 7.48 (1H, s), 7.61 (1H, s) 

(4) 5-[3-(Amino)propylamino]imidazo[1 ,2-a]pyridine 

NMR (90MHz, CDCI3) 5: 1.57 (2H, br), 1.87 (2H, m), 3.01 (2H, m), 3.39 (2H, m), 5.78 (1H, dd, J = 7, 1.5Hz), 
35 6.78 (1H, br), 6.96-7.28 (2H, m), 7.38 (1H, s), 7.59 (1H, s) 

Reference Example 8 

Synthesis of 5-[3-(amino)propylamino]imidazo[1 ,2-a]pyridine*dihydrochloride 

40 

To a suspension of 5-[3-(tert-butoxycarbonylamino)propylamino]imidazo[1 ,2-a]pyridine (1.742 g, 6 
mmoles) in methylene chloride (40 mi) was added hydrogen chloride-methanol (6 ml) and the mixture was 
stirred at room temperature for 20 hours. After the solvent was distilled off, ethanol (15 ml) and ether (30 ml) 
were added to the residue. Then, the crystals precipitated were filtered off and washed in turn with ether 
45 and a small amount of ethanol to obtain 1.311 g of the desired product (83.0%, pale yellow crystals). 



Elemental analysis for CioHi4N 4 0 # 2HCl # 0.2H 2 0, 


Calcd.: 
Found : 


C, 45.02; 
C, 45.15; 


H, 6.20; 
H, 6.25; 


N, 21.00 
N, 21.17 



NMR (90MHz, DMSO-d 6 ) 6: 2.02 (2H, m), 2.95 (2H, m), 3.52 (2H, m), 6.53 (1H, d, J=8Hz), 7.08 (1H, d, 
J = 8.5Hz), 7.79 (1H, dd, J =8.5, 8Hz), 8.12 (1H, d J = 2Hz), 8.27 (3H, br), 8.53 (1H, br), 8.78 (1H, d, J = 2Hz) 

55 

Reference Example 9 

Synthesis of 5-[3-(amino)propylthio]imidazo[1 ,2-a]pyridine 

22 

3MSDOCID <;EP 0471238A1 I > 



EP 0 471 236 A1 



To a mixed solution of 10% potassium hydroxide (69.3 g, 105 mmoles) and dimethy [sulfoxide (50 ml) 
was added S-[3-(amino)propyl]isothiourea 'dihydrobromide (8.85 g, 39 mmoles) and the mixture was stirred 
at room temperature for 1.5 hours. To the reaction solution was added 5-chloroimidazo[1 ,2-a]pyridine (3.05 
g, 20 mmoles), followed by stirring at room temperature for 1.5 hours and additional stirring at 65* C for 20 
5 hours. Water was added to the reaction solution, which was extracted with chloroform, washed several times 
with 1N-sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off to 
obtain 2.66 g of the desired product (64.3%, pale yellow oily product). 

NMR (200MHz, CDCI 3 ) 5: 1.29 (2H, br), 1.80 (2H, m), 2.85 (2H, t, J = 6.8Hz), 3.08 (2H, t, J = 7.2Hz), 6.91 (1H, 
dd, J = 7, 1Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.58 (1H, d, J = 9, 1Hz), 7.71 (1H, d, J = 1 .2Hz), 7.85 (1H, d, 
w J = 1.2Hz) 

Reference Example 10 



According to the same manner as that described in Reference Example 8, the following compounds 
75 were obtained. 

(1) 5-[2-(Amino)ethylsulfonyl]imidazo[1,2-a]pyridine*dihydrochloride Melting point: 210-220* C (dec.) 



20 


Elemental analysis for C9H1 1 N 3 0 2 S*2HCI' 0.5H 2 O, 




Calcd.: 


C, 35.19; 


H, 4.59; 


N, 13.68 




Found : 


C, 35.18; 


H, 4.49; 


N, 13.98 



25 

(2) 5-[2-(Amino)ethylsulfinyl]imidazo[1 ,2-a]pyridine * dihydrochloride 



Melting point: 1 95-205 "C (dec.) 



Elemental analysis for C 9 Hi , N 3 OS*2HCI *0.3H 2 O, 


Calcd.: 
Found : 


C, 37.59; 
C, 37.76; 


H, 4.77; 
H, 4.77; 


N, 14.61 
N, 14.60 



(3) 5-[2-(Amino)ethoxy]imidazo[1 ,2-a]pyridine' dihydrochloride 
Melting point: 209-220 "C (dec.) 



Elemental analysis for C 9 Hi ! N 3 0*2HCrH 2 0, 


Calcd.: 
Found : 


C, 40.31; 
C, 40.20; 


H, 5.64; 
H, 5.65; 


N, 15.67 
N, 15.58 



(4) 5-[4-(Piperidyl)thio]imidazo[1 ,2-a]pyridine' dihydrochloride 



f 1 i.! ' ' 








' I n O 




Calcov. 


C. 


47.06; 


H, 5.59; 


N. 


13.72 


Found : 


c 


47.00; 


H, 5.63; 


N. 


13 56 



EP 0 471 236 A1 



Synthesis of 5-[2-(amino)ethy!thio]imidazo[1 ,2-a)pyridine 

After a suspension of 5-[2-(amino)ethy!thio]imidazo[1 ,2-a]pyndine"dihydrochloride (13.31 g, 50 
mmoles) in chloroform (200 m!) was washed with 3N-sodium hydroxide (50 ml), the aqueous layer was 
5 extracted with chloroform, combined the chloroform layer was dried over anhydrous magnesium sulfate. 
After the solvent was distilled off to obtain 9.63 g of the desired product (99.7%, pale yellow oily product). 
NMR (200MHz, CDCI 3 ) 5: 1.67 (2H, br), 2.95 (2H, m), 3.08 (2H, m), 6.95 (1H, d, J = 7Hz), 7.15 (1H, dd, 
J = 9.2, 7Hz), 7.59 (1H, d, J = 9.2Hz), 7.71 (1H, s), 7.88 (1H, s) 

70 Reference Example 12 

Synthesis of 5-[3-(chloro)propylthio]imidazo[1 ,2-a]pyridine 

To a suspension of 5-mercaptoimidazo[1 ,2-a]pyridine (5.02 g, 33.4 mmoles) and 1-brorno-3- 
75 chloropropane (5.26 g, 33.4 mmoles) in ethanol (100 ml) was added triethylamine (4.66 ml, 33.4 mmoles) 
and the mixture was stirred at room temperature for 17 hours. After the solvent was distilled off, chloroform 
was added to the residue, which was washed with water and dried over anhydrous magnesium sulfate. After 
the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to 
obtain 5.46 g of the desired product (72.0%, light brown oily product). 
20 NMR (200MHz, CDCI3) 5: 2.09 (2H, m), 3.17 (2H, t, J = 7Hz), 3.68 (2H t t, J=6Hz), 6.94 (1H, dd, J = 7.2, 
1Hz), 7.16 (1H, dd, J = 9.2, 7.2Hz). 7.60 (1H, m), 7.72 (1 H, d, J = 1.2Hz), 7.86 (1H, m) 

Example 1 

25 Synthesis of 5-[2-(methylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 1) 

To a solution of 5-[2-(amino)ethylthio]imidazo[1 ,2-a]pyridine (9.63 g, 49.8 mmoles) and triethylamine 
(7.64 ml) in methylene chloride (150 ml) was added methanesulfonyl chloride (3.85 ml, 49.7 mmoles) with 
stirring under ice-cooling and was stirred under ice-cooling for 1 hour. The reaction solution was poured into 
30 water and stirred. Then, the crystals precipitated were filtered off, washed with water and dried to obtain 
10.53 g of the desired product (77.9%, colorless crystals). 
Melting point: 130-131 * C 



Elemental analysis (%) for C1 0H1 3N3O2S2, 


Calcd.: 
Found : 


C, 44.26: 
C, 44.05; 


H, 4.83; 
H, 4.82; 


N, 15.48 
N, 15.31 



NMR (90MHz, DMSO-d G ) 5: 2.96 (3H, s), 3.22 (4H, s), 7.10 (1H. dd, J = 7, 1.5Hz), 7.26 (1H. dd, J = 9, 7Hz), 
7.31 (1 H, br), 7.56 (1 H, d, J = 9Hz), 7.68 (1 H, d, J = 1 Hz), 7.97 (1 H, s) 
IR (KBr) cm" 1 : 3450, 3140, 2930, 1620, 1490, 1315, 1155 

Example 2 

Synthesis of 5-[2-(methylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine* hydrochloride (Compound 2) 

A suspension of 5-[2-(methylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine (543 g, 2 mmoles) in metha- 
nol (20 ml) was treated with hydrogen chloride-methanol. After the solvent was distilled off, the residue was 
crystallized from chloroform ether. Then, the crystals thus obtained were washed with ether and dried to 
obtain 550 mg of the desired product (89.3%, colorless crystals). 
Melting point: 154-160" C 

Example 3 

(1) Synthesis of 5-[2-(ethylsulfony!amino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 3) 

To a solution of 5-[2-(amino)ethylthio]imidazo[1 ,2-a]pyridine (1.93 g, 10 mmoles) and triethylamine (1.53 
ml, 11 mmoles) in methylene chloride (100 ml) was added ethanesulfony! chloride (0.95 ml, 10 mmoles) at 

24 



BNSDOCID: <EP 0471 236A1 



EP 0 471 236 A1 



room temperature with stirring and the mixture was stirred at room temperature for 1 hour. The reaction 
mixture was washed in turn with an aqueous saturated sodium bicarbonate solution and water and dried 
over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by 
column chromatography (eluent: ethanol/ethyl acetate = 1:5) to obtain 2.23 g of the desired product 
5 (78.2%, colorless crystals). 





Elemental analysis for Ci , 5 N 3 0 2 S 2 - 0.1 H 2 0, 




Calcd.: 


C, 46.01; 


H, 5.34; 


N, 14.63 


70 


Found : 


C, 45.74; 


H, 5.26; 


N, 14.36 



NMR (90MHz, DMSO-d & ) 5: 1.16 (3H, t. J = 7Hz), 2.99 (2H, q, J = 7Hz). 3.21 (4H, m), 7.11 (1H, dd, J = 7, 
1.5Hz), 7.28 (1H, dd, J = 8.5, 7Hz), 7.33 (1H, br), 7.59 (1H, d, J = 8.5Hz), 7.71 (1H, s), 7.99 (1H, s) 

According to the same manner as that described in Example 3 (1), the following compounds were 
obtained. 

(2) 5-[2-(Propylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 4) 



Elemental analysis for Ci 2H 17 N 3 O2S*0.2H2O, 


Calcd.: 
Found : 


C, 47.57; 
C, 47.62; 


H, 5.79; 
H, 5.74; 


N, 13.87 
N, 14.03 



NMR (200MHz, CDCI 3 ) 8: 1.04 (3H, t, J = 7.4Hz) ( 1.83 (2H, m), 2.98 (2H, m), 3.19 (2H, m), 3.33 (2H, m), 4.93 
(1H, br), 7.02 (1H, dd, J = 7, 1.2Hz), 7.17 (1H, dd, J = 9, 7Hz), 7.63 (1H, m), 7.70 (1H, d, J = 1.4Hz), 7.85 (1H, 
m) 

30 (3) 5-[2-(lsopropylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 5) 

NMR (200Hz, CDCI 3 ) 6: 1.36 (6H, d, J = 6.8Hz), 3.16 (1H, heptet, J = 6.8Hz), 3.19 (2H, t, J = 6.4Hz), 3.36 (2H, 
m), 4.80 (1H, br), 7.02 (1H, dd, J = 7, 1.2Hz), 7.17 (1 H, dd. J = 9, 7Hz), 7.62 (1H, d, J = 9Hz), 7.70 (1H, s), 
7.86 (1H, m) 

35 

(4) 5-[2-(Butylsulfonylamino)ethylthio]imidazo[1.2-a]pyridine (Compound 6) 



Elemental analysis for Ci 3 Hi° 


N3O2S2, 


Calcd. : 


C, 49.82; 


H, 6.11; 




N, 13.41 


Found : 


C, 49.76; 


H, 6.15; 




N, 13.40 



NMR (200Hz, CDCI3) 6: 0.93 (3H, t, J = 7.2Hz), 1.43 (2H, m), 1.76 (2H, m), 3.00 (2H, m), 3.19 (2H, m), 3.33 
(2H, m), 5.06 (1H, br), 7.01 (1H, dd, J = 7, 1.2Hz), 7.16 (1 H, dd, J = 9, 7Hz), 7.61 (1H, d, J = 9Hz), 7.69 (1H, 
d, J = 1.2Hz), 7.84 (1H, m) 



(6) 5-[2-[3-(Chloro)propylsulfonylamino]ethylthio]imidazo[1 ,2-a]pyridine (ComDOund 8) 



EP 0 471 236 A1 



Elemental analysis for 2 Hi e N 3 0 2 S 2 CI 


Calcd.: 
Found : 


C, 43.17; 
C, 43.41; 


H, 4.83; 
H, 4.83; 


N, 12.59 
N, 12.47 



NMR (90Hz, CDCI 3 -DMSO-d 6 ) 5: 2.22 (2H, m), 2.97-3.46 (6H ( m), 3.66 (2H, t, J = 6.5Hz), 7.07 (1 H dd 
J = 7.5. 2Hz), 7.19 (1H, dd, J = 9, 7.5Hz), 7.26 (1H, br), 7.59 (1H, m), 7.69 (1H, s), 7.90 (1H, s) 

(7) 5-[2-(Hexadecylsulfonylamino)ethylthio]imidazo[1,2-a]pyridine (Compound 9) 

NMR (200Hz, CDCI 3 ) <5: 0.88 (3H, t, J = 6.8), 1.25 (26H, m), 1.78 (2H, m), 3.00 (2H, m), 3.18 (2H, m), 3.33 
(2H, m), 4.73 (1H, br), 7.02 (1 H. dd, J = 7.1 Hz), 7,17 (1H, dd, J = 9, 7Hz), 7.64 (1H, d, J = 9Hz) 7 72 (1H d 
J = 1 .2Hz), 7.87 (1 H, s) 

Example 4 

(1) Synthesis of 3-chloro-5-[2-(methylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 10) and 3- 
chloro-5-[2-(methylsulfonylamino)ethylthio]-2-succinimide-imidazo[1 ,2-a]pyridine (Compound 11) 

To a suspension of 5-[2-(methylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine (534 mg, 2 mmoles) in 
chloroform (60 ml) was added N-chlorosuccinimide (267 mg, 2 mmoles) at room temperature with stirring 
and the mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with water 
and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was 
purified by column chromatography (eluent: ethanol/ethyl acetate = 1:10) to obtain 245 mg of the desired 
product (Compound 10, 40.0%, gray crystals) as Fraction 1. 





Elemental analysis for C1 oHi 2 N3 02S 2 CI, 


30 


Calcd.: 


C, 39.28; 


H, 3.96; 


N, 13.74 


Found : 


C, 39.47; 


H, 4.00; 


N, 13.61 



NMR (90MHz, DMSO-d G ) 5: 2.90 (3H, s), 3.22 (4H, m), 7.06 (1H, dd, J = 7, 1.5Hz), 7.23 (1H, dd, J = 9, 7Hz), 
7.53 (1 H, dd, J = 9, 1 .5Hz), 7.66 (1 H, s) 

As Fraction 2, 96 mg of the desired product (Compound 11, 11.9%, colorless crystals) was obtained. 
NMR (90MHz, DMSO-d 6 ) 5: 2.94 (3H, s), 2.97 (4H, s), 3,23 (4H, m), 7.19 (1H, dd, J = 7, 2Hz), 7.40 (1H dd 
J = 9, 7Hz), 7.59 (1 H, dd, J = 9, 1 .5Hz) 

According to the same manner as that described in Example 4 (1), the following compounds were 
obtained. 

(2) 3-Bromo-5-[2-(methylsulfonylamino)ethylthio]imidazo[1,2-a]pyridine (Compound 12) 



45 


Elemental analysis for CioHi 2 N 3 0 2 S 2 Br, 




Calcd.: 


C, 34.29; 


H, 3.45; 


N, 12.00 




Found : 


C, 34.26; 


H, 3.45; 


N, 11.94 



NMR (90MHz, DMSO-d 6 ) 5: 2.90 (3H, s), 3.19 (4H, m), 7.07 (1H, dd, J = 7, 1.5Hz), 7.23 (1H, dd, J = 9, 7Hz), 
7.56 (1 H, dd, J = 9, 1 .5Hz), 7.66 (1 H, s) 

(3) 3-lodo-5-[2-(methylsulfonylamino)ethylthio)imidazo[1,2-a]pyridine (Compound 13) 

NMR (90MHz, DMSO-d 6 ) 5: 2.98 (3H, s), 3.17 (4H, m), 7.07 (1H, dd, J = 7, 1.5Hz), 7.24 (1H, dd, J = 9, 7Hz), 
7.60 (1H, dd, J = 9, 1.5 Hz), 7.68 (1H, s) 

Example 5 



26 

BNJSDOCID: <EP 0471 236A1 .. I_> 



EP 0 471 236 A1 



Synthesis of 5-[2-(methylsulfonylamino)ethylthio]-3-morpholinomethy)imtdazo[1 ( 2-a]pyridine (Compound 14) 

To a solution of 37% formalin (178 mg, 2.2 mmoles) in acetic acid (2 ml) was added morpholin (192 ul, 
2.2 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes 

5 5-[2-(methylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyndine (543 mg, 2 mmoles) was added to the reaction 
mixture, followed by stirring at 60 "C for 2 hours After the solvent was distilled off, the residue was 
dissolved in chloroform (50 ml) and washed with 1N NaOH (10 ml). Then, the aqueous layer was extracted 
with chloroform (30 ml x 3) and the combined chloroform layer was dried over anhydrous magnesium 
sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent 

to ethanol/ethyl acetate = 1:10 — 1:5) to obtain 530 mg of the desired product (71.5%, colorless solid). 

NMR (90MHz, CDCI 3 ) 6: 2.94 (4H, m), 2.67 (3H, s). 3.27 (4H, m). 3.67 (4H, m), 4.08 (2H, s), 6.62 (1H, br). 
6.94 (2H, m), 7.50 (1H, s), 7.57 (1H, dd, J =8.5, 2Hz) 

Example 6 

75 " 

According to the same manner as that described in Example 4 (1), the following compounds were 
obtained. 

5-[2-(Methylsulfonylamino)ethylthio-3-morpholinomethylimidazo[1 ,2-a]pyridine dihydrochloride 
20 (Compound 15) 

NMR (200MHz, DMSO-d&) 5: 2.92 (3H, s), 3.15-4.20 (14H, m), 5.08 (1H, br), 7.44 (1H, m), 7.69 (1H, dd, 
J = 7, 1 .4Hz), 7.83 (1 H, dd, J = 8.7, 7Hz), 7.94 (1 H, dd, J = 8.8, 1 .4Hz), 8.40 (1 H, s) 

Example 7 

25 

According to the same manner as that described in Examples 2 and 5, the following compounds were 
obtained. 

3-Dimethylaminomethyl-5-[2-(methylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine' dihydrochloride 
30 (Compound 16) 





Elemental analysis for Ci 3 H 2 oN4 02S 


2 *2HCI, 


35 


Calcd.: 


C, 38.05; 


H, 5.65; 


N, 13.65 




Found : 


C, 38.33; 


H. 5.65; 


N, 13.61 



NMR (90MHz, DMSO-d^-DjO) 6: 2.95 (9H, s), 3.30 (4H, m), 5.08 (2H. s), 7.68-8.06 (3H, m), 8.43 (1H t s) 
Example 8 



According to the same manner as that described in Example 3, the following compounds were obtained 
(1) 2-Methyl-5-(2-methylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 17) 
Melting point: 179-181 ' C 



EP 0 471 236 A1 



s) 

(3) 3-Ethoxycarbonyl-2-methyl-5-[2-(methyisulfonylamino)ethylthio]imidaz 
(Compound 19) 

5 

NMR (90MHz, CDCI 3 ) 5; 1.40 (3H, t, J=7Hz), 2.60 (3H, s), 2.85 (3H, s), 3.21 (4H, m), 4.43 (2H, q, J = 7Hz), 
5.20 (1H, br), 7.07 (1H, dd, J = 7, 1.5Hz), 7.33 (1H, dd, J = 9, 7Hz), 7.51 (1H, dd, J = 9, 1.5Hz) 

(4) 2-Ethoxycarbonyl-5-[2-(methylsulfonylamino)ethylthio]imidazo[1,2-a]pyridine (Compound 20) 

70 

NMR (90MHz, DMSO-d 6 ) 6: 1.34 (3H, t, J = 7Hz), 2.92 (3H, s), 3.26 (4H, m), 4.30 (2H, q, J = 7Hz), 7.23 (1H, 
dd, J = 7, 1 Hz), 7.30 (1 H, br), 7.39 (1 H, dd, J = 9, 7Hz), 7.64 (1 H, d, J = 9Hz), 8.43 (1 H, s) 

Example 9 

75 

Synthesis of 2-carboxymethyl-5-[2-(methylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 21) 

To a solution of 2-ethoxycarbonyl-5-[2-(methylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine (1.65 g, 
4.62 mmoles) in methanol (5 ml) was added 1N NaOH (6.93 ml, 6.93 mmoles) and the mixture was stirred 
20 at room temperature for 2.5 hours. After the reaction mixture was washed with methylene chloride, 1N HCI 
(17.39 ml, 17.39 mmoles) was added thereto and the solvent was distilled off. Water was added to the 
residue and the resulting solid was washed with water and dried to obtain 777 mg of the desired product 
(51.1%, colorless solid). 



Elemental analysis for Ci 2H1 5N3O4.S2 


Calcd.: 
Found : 


C, 43.76; 
C, 43.68; 


H, 4.59; 
H, 4.60; 


N, 12.76 
N, 12.64 



NMR (200MHz, DMSO-de) 5: 2.92 (3H, s), 3.24 (4H, s), 3.75 (2H, s), 7.09 (1H, dd, J = 7.2, 1Hz), 7.27 (1 H, 
dd, J = 9, 7.2Hz), 7.36 (1 H, br), 7.48 (1 H, d, J = 9Hz), 7.86 (1 H, s) 

Example 10 

According to the same manner as that described in Examples 2 and 3 (1), the following compounds 
were obtained. 

(1) 5-[2-(N-Methyl-N-methylsulfonylamino)ethylthio]imidazo[1,2-a]pyridine (Compound 22) 

NMR (200Hz, CDCh) 5: 2.82 (3H, s), 2.89 (3H, s), 3.22 (2H, m), 3.40 (2H, m), 7.03 (1H, dd, J = 7, 1 Hz), 7.19 
(1 H, dd, J = 9, 7Hz), 7.62 (1 H, d, J = 9Hz), 7.72 (1 H, d, J = 1 .2Hz), 7.86 (1 H, s) 

(2) 5-[2-(N-methyl-N-methylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine* hydrochloride 
(Compound 23) 

Melting point: 152-154* C 



(3) 5-[2-(methylsulfonylamino)ethylsulfinyl]imidazo[1 ,2-a]pyridine (Compound 24) 

50 





Elemental analysis for Ci 0H1 3N3O3S2 "2H2O, 




Calcd.: 


C, 41.28; 


H, 4.64; 


N, 14.44 


55 


Found : 


C, 41.48; 


H, 4.57; 


N, 14.66 



NMR (200Hz, CDCI 3 -DMSO-d & ) 5: 2.98 (3H, s), 3,16-3.33 (1H, m), 3.39-3.76 (3H, m), 7.33-7.47 (3H, m), 
7.33-7.84 (2H, m), 8.03 (1H, m) 



28 

BNSDOCID: .EP __ 0471 236A1 _\_> 



EP 0 471 236 A1 

(4) 5-[2-{Methylsulfonylammo)ethylsu!fonyl]imidazo[1 ,2-aJpyridine (Compound 25) 



Elemental analysis for Ci c Hi 3N3O4 S2. 


Calcd.: 
Found : 


C, 39.59; 
C, 39.31; 


H, 4.32; 
H, 4.33; 


N, 13.85 
N, 13.78 



NMR (200Hz, CDCI 3 -DMSO-d & ) 5: 2.88 (3H, s), 3.45-3.66 (4H, m), 7.40 (1H, d, J = 9, 7Hz), 7.71 (1H, dd, 
J = 7, 1 .2Hz), 7.85 (1 H; d, J = 1 .2Hz), 7.96 (1 H, d, J = 9Hz), 8.30 (1 H, s) 

(5) 5-[2-(Trifluoromethylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 26) 

NMR (90Hz, DMSO-d&) 6: 3.12-3.52 (4H, m), 7.13 (1H, dd, J = 7, 1.5Hz), 7.28 (1H, dd, J = 9, 7Hz), 7.61 (1H, 
d, J = 9Hz), 7.71 (1H, d, J = 1.5Hz), 8.02 (1H, s) 

(6) 5-[3-(Methylsulfonylamino)propylthio]imidazo[1 ,2-a]pyridine (Compound 27) 



Elemental analysis for C1 1 H15N3O2S2, 


Calcd.: 
Found : 


C, 46.29; 
C, 46.35; 


H, 5.30; 
H, 5.34; 


N, 14.72 
N, 14.71 



NMR (90Hz, CDCI3) 5: 1-90 (2H, m), 2.93 (2H, s), 3.07 (2H, m), 3.27 (2H, m), 5.54 (1H, br), 6.90 (1H, dd, 
J = 7, 1 Hz), 7.1 1 (1 H, dd, J = 9, 7Hz), 7.57 (1 H, d, J = 9Hz), 7.65 (1 H, d, J = 1 .5Hz), 7.82 (1 H, s) 

(7) 5-[3-(Trifluoromethylsulfonylamino)propytthio]imidazo[1 ,2-a]pyridine (Compound 28) 



Elemental analysis for C1 1 H12N3O2S2F3, 


Calcd.: 
Found : 


C, 38.93; 
C, 38.91; 


H, 3.56; 
H, 3.64; 


N, 12.38 
N, 12.27 



NMR (200Hz, CDCIa-DMSO-du) 5: 1.91 (2H, m), 3.09 (2H, t. J = 7.2Hz), 3.36 (2H. t, J = 6.2Hz), 6.97 (1H, dd, 
J = 7, 1Hz), 7.19 (1H, dd. J = 9. 7Hz). 7.58 (1H, dd, J = 9, 1Hz), 7.70 (1H, d, J = 1.2Hz), 7.88 (1H, s) 

(8) 5-[1-(Methylsulfonyl)-4-piperidylthio]innidazo[1 ,2-a]pyridine * hydrochloride 
(Compound 29) 

Melting point: 191-200" C 

NMR (200Hz, CDC! 3 ) of the free compound 5: 1.70-2.13 (4H, m). 2.79 (3H s), 2.90 (2H, m), 3.35 (1H, m), 
3.69 (2H, m), 7.05 (1H, dd, J = 7, 1.2Hz), 7.17 (1H, dd, J = 8.8, 7Hz), 7.67 (1H, d, J = 8.8Hz), 7.71 (1H, d, 
J = 1.2Hz), 7.96 (1H, s) 



Calcd.: 
Found 



ntiii analysis 

C, 54.03; 

C, 53.88; 



. H- , N.i 



H, 4.53; 
H. 4.53; 



N. 12.60 
N. 12.43 



EP 0 471 236 A1 

(10) 5-[2-[4-(Methyl)phenylsulfonylamino]ethylthio]imidazo[1,2-a]pyridine (Compound 31) 



5 


Elemental analysis for Ct 6 Hi 7 N 3 0 2 S 2 •0.5H 2 O, 




Calcd.: 


C, 53.91; 


H, 5.09; 


N. 11.79 




Found : 


C, 54.13; 


H, 4.94; 


N, 11.57 



NMR (90Hz, CDCI 3 -DMSO-d 6 ) 6: 2.39 (3H, s), 3.16 (4H, m), 6.90-7.33 (3H, m), 7.47-7.90 (7H, m) 
(11) 5-[2-[4-(Acetamido)phenylsulfonylamino]ethylthio]imidazo[1 ,2-a]pyridine (Compound 32) 



75 


Elemental analysis for C17H18N4O 


3S2MH2O. 




Calcd.: 


C, 49.98; 


H, 4.93; 


N, 13.72 




Found : 


C, 50.16; 


H, 4.60; 


N, 13.60 



20 NMR (200Hz, DMSO-d 5 ) 5: 2.09 (3H, s), 2.98 (2H, m), 3.13 (2H, m) f 6.99 (1H, dd, J = 1 Hz), 7.23 (1H, dd, 
J = 9, 7Hz), 7.52-7.77 (6H, m), 7.83 (1H, br), 7.90 (1H, m) 

(12) 5-[2-[4-(Acetamido)phenylsulfonylamino]ethylthio]imldazo[1 ,2-a]pyridine* hydrochloride 
(Compound 33) 

25 

Melting point: 126-130* C 

(13) 5-[2-[4-(Chloro)phenylsulfonylamino]ethylthio]imidazo[1 ,2-a]pyridine (Compound 34) 



Elemental analysis for CisHi4N 3 O 2 S2Cr0.5H2O, 


Calcd.: 
Found : 


C, 47.80; 
C, 48.03; 


H, 4.01; 
H, 3.63; 


N, 11.15 
N, 11.18 



NMR (200Hz, CDCb-DMSO-ds) 5: 3.68 (4H, m), 6.98 (1H, d, J = 7Hz), 7.18 (1H, dd, J = 9, 7Hz), 7.44 (2H, 
m), 7.56 (1 H, d, J = 9Hz), 7.67 (1 H, d, 1 .2Hz), 7.74 (2H, m), 7.83 (1 H, s), 7.87 (1 H, br) 

(14) 5-[2-[4-(FIuoro)pheny!sulfonylamino]ethylthio]imidazo[1,2-a]pyridine (Compound 35) 



Elemental analysis for C15H14N3O2S2F 


Calcd.: 
Found : 


C, 51.27; 
C, 51.16; 


H, 4.02; 
H, 4.05; 


N, 11.96 
N, 12.05 



NMR (200Hz, CDC1 3 -DMSO-d s ) 6: 3.08 (4H, m), 6.95 (1H, dd, J = 7, 1Hz), 7.07-7.20 (3H, m), 7.48 (1H, br), 
7.58 (1 H, d, J = 9Hz), 7.68 (1 H, d, J = 1 .2Hz), 7.77-7.86 (3H, m) 

50 

(15) 5-[2-[4-(Methoxy)phenylsulfonylamino]ethylthio]imidazo[1,2-a]pyridine (Compound 36) 



55 


Elemental analysis for Ci gHi 7N3O3S2 *0.3H 2 O, 




Calcd.: 


C, 52.10; 


H, 4.81; 


N, 11.39 




Found : 


C, 52.25; 


H, 4.73; 


N, 11.47 



30 



BNSDOC1D: <EP 0471235A1 I > 



EP 0 471 236 A1 



NMR (200Hz, CDCb-DMSO-ds) 5: 3.07 (4H, m), 3.86 (3H, s), 6.86-6.97 (3H, m), 7.15 (1H, dd, J = 9, 7Hz), 
7.20 (1H, br), 7.57 (1H, d, J = 9Hz), 7.64-7.76 (3H, m), 7.81 (1H, s) 

(16) 5-[2-[2 ! 4,5-(Trichloro)phenylsulfonylamino]ethylthio]imidazo[1 ,2-a)pyridine (Compound 37) 

5 





Elemental analysis for Ci 5H1 2N3O2S2CL3 'O.SKfeO, 




Calcd.: 


C, 40.42; 


H, 2.94; 


IN, 9.43 


70 


Found : 


C, 40.65; 


H, 2.74; 


N, 9.50 



NMR (200Hz. CDCh-DMSO-ds) S: 3.07-3.25 (4H, m), 6.95 (1H, dd, J = 7, 1Hz), 7.16 (1H. dd, J = 9, 7Hz), 
7.57 (1H, d, J = 9Hz), 7.59 (1H, s), 8.07 (1H, s) 

(17) 5-t2-[2,4,6-(Trimethyl)phenylsulfonylamino]ethylthio)imidazo[1,2-a]pyridine (Compound 38) 





Elemental analysis for C18H21 N3O2S2, 


20 


Calcd.: 


C, 57.57; 


H. 5.65; 


N, 11.19 




Found : 


C, 57.32; 


H, 5.65; 


N, 11.09 



NMR (200Hz, CDCI3) 5: 2.30 (3H, s), 2.58 (6H, s), 2.98-3.20 (4H. m), 5.00 (1H, br), 6.81 (1H, d, J = 7Hz), 
25 6.92 (2H, s), 7.08 (1H, dd, J = 9, 7Hz), 7.60 (1H, d, J = 9Hz), 7.68 (1H, s), 7.77 (1H, s) 

(18) 5-[2-[2,4,6-(Triisopropyl)phenylsulfonylamino]ethylthio]imidazo[1 ,2-a]pyridine 
(Compound 39) 



Elemental analysis for C2*H33N 3 02S 2 , 


Calcd.: 
Found : 


C, 62.71; 
C, 62.65; 


H, 7.24; 
H, 7.15; 


N, 9.14 
N, 9.07 



NMR (200Hz, CDCI3) 5: 1.24 (12H, d, J=6.8Hz), 1.26 (6H, d, J = 7Hz), 2.94 (1H, heptet. J = 7Hz), 3.06-3.25 
(4H, m), 4.10 (2H, heptet, J = 6.8Hz), 4.90 (1H, br), 6.83 (1H, dd, J = 7, 1Hz), 7.08 (1H, dd, J = 9, 7Hz), 7.59 
(1H, d. J = 9Hz), 7.68 (1H, d, J = 1 .2Hz), 7.80 (1H. m) 

(19) 5-[2-[(2-Thienyl)sulfonylamino]ethylthio]imidazo[1 ,2-a]pyridine (Compound 40) 





Elemental analysis for C13H13N: 


J02S3, 


45 


Calcd.: 


C, 46.00; 


H, 3.86; 


N, 12.38 




Found : 


C, 45.71; 


H, 3.88; 


N, 12.30 



(20; b-[2-[(2- 1 nienyljSJitoryiamtnoloihyitmojimidazoL 1 ,2-a jpyndine hyurocn on,Ju 
(Compound 4 1 ) 



EP 0 471 236 A1 



Elemental analysts for C13H13N3O2! 


3 3 


•HCI, 


Calcd.: 


C, 41.54; 


H, 3.75; 




N, 11.18 


Found : 


C, 41.25; 


H, 3.80; 




N, 11.05 



(21) 5-[2-[(1-Naphthyl)sulfonylamino]ethylthio]imidazo[1,2-a]pyridine (Compound 42) 



Elemental analysis for C19H1 7N3O2S2, 


Calcd.: 
Found : 


C, 59.51; 
C, 59.73; 


H. 4.47; 
H, 4.61; 


N, 10.96 
N, 10.77 



NMR (200Hz, CDCI 3 ) 5: 2.97 <2H, m), 3.07 (2H, m), 5.55 (1H, br), 6.56 (1H, dd. J = 7, 1Hz), 6.92 (1H, dd 
J = 9, 7Hz), 7.44-7.72 (6H, m), 7.96 (1H, m), 8.06 (1H, d, J = 8.2Hz), 8.20 (1H, dd, J = 7.4, 1 .2Hz) 8 64 (1H 
m) 

(22) 5-[2-[(1 -Naphthyl)sulfonylamino]ethylthio]imidazo[1 ,2-a]pyridine hydrochloride 
(Compound 43) 

Melting point: 1 79-1 85 "C 

(23) 5-[2-[(2-Naphthyl)sulfonylamino]ethylthio]imidazo[1,2-a]pyridine (Compound 44) 
Melting point: 179-185* C 



Elemental analysis for Ci 3 Hi 7N3O2S2 *0.2H2O, 


Calcd.: 
Found : 


C, 58.95; 
C, 59.15; 


H, 4.53; 
H, 4.78; 


N, 10.86 
N, 10.55 



NMR (200Hz, CDCI3) 5: 3.07 (2H, m), 3.20 (2H. m), 5.31 (1H, br), 6.74 (1H, dd, J = 7, 1 Hz), 6.89 (1H dd 
J = 9, 7Hz), 7.51 (1H, d, J = 9Hz), 7.58-7.85 (5H, m), 7.88-7.97 (3H, m), 8.39 (1H, d, J = 1 6Hz) 

(24) 5-[2-[(2-Naphthyl)sulfonylamino]ethylthio]imidazo[1,2-a]pyridine* hydrochloride 
(Compound 45) 

Melting point: 170-175* C 

(25) 5-[2-[(8-Quinolyl)sulfonylamino]ethylthio]imidazo[1,2-a]pyridine (Compound 46) 



45 


Elemental analysis for Ci 8 Hi e N4O2S2 




Calcd.: 


C, 56.23; 


H, 4.19; 


N, 14.57 




Found : 


C, 56.39; 


H, 4.23; 


N, 14.69 



50 NMR (200Hz, CDCI 3 ) S: 3.00-3.22 (4H, m), 6.65 (1H, dd, J = 7, 1Hz), 6.81 (1H, br), 6.97 (1H, dd, J = 9, 7Hz), 
7.47-7.74 (5H, m ), 8.06 (1H, dd, J = 8.4, 1.4Hz), 8.26 (1H, dd, J = 8.4, 1.8Hz), 8.40 (1 H, dd J = 7 2 1 4Hz) 
8.95 (1H, dd, J = 4.2, 1.8Hz) 

(26) 5-[2-[8-(Quinolyl)sulfonylamino]ethylthioimidazo[1 ,2-a]pyridine" hydrochloride 
55 (Compound 47) 

Melting point: 190-196* C 



32 

BNSDOCID; <EP C471236A1 I 



EP 0 471 236 A1 



(27) 5-[2-[5-(Dimethylamino)-(1-naphthylsulfony!amino)]ethylthio]irrii(jazo[l ,2-a]pyndine (Compound 48) 

NMR (200Hz, CDC! 3 ) 5: 2.90 (6H, s), 2.93-3.12 (4H, m), 5.46 (1H, br), 6.56 (1H, dd, J = 7, 1Hz), 6.92 (1H, dd, 
J = 9, 7Hz), 7.19 (1H, d, J = 7.6Hz), 7.43-7.63 (4H, m), 7.67 (1H, s), 8.18 (1H, dd, J = 7.4, 1.2Hz), 8.27 (1H, d, 
5 J = 8.6Hz), 8.53 (1 H, d, J = 8.6Hz) 

(28) 5-[2-[(E)-Styrylsu!fonylamino]ethylthio]iinidazo[1 ,2-a]pyridine (Compound 49) 



Elemental analysis for Ci 7 Hi 7^0282, 


Calcd.: 
Found : 


C, 56.80; 
C, 56.95; 


H, 4.77; 
H, 4.84; 


N, 11.69 
N, 11.62 



75 NMR (200Hz, CDCb) 5: 3.14-3.34 (4H, m), 4.95 (1H, br), 6.70 (1H, d, J = 15.4Hz), 6.98 (1H, dd, J = 7, 1Hz), 
/.uy (1H, dd, J = 9, /Mz), /.43 (5H, m), 7.46 (iH, d, J= i5.4Hz), 7.59 (l H, d, J =9Hzj, 7.66 (1 H, d, J = 1 .4Hz), 
7.84 (1H.s) 

(29) 5-[2-[N,N-di-(E)-Styrylsulfonylamino]ethylthio]im>dazo[1,2-a]pyridine (Compound 50) 



Elemental analysis for C 25 ^sNaCUSs, 


Calcd.: 
Found : 


C, 57.12; 
C, 57.07; 


H, 4.41; 
H, 4.48; 


N, 7.99 
N, 7.81 



NMR (200Hz, CDCb) 5: 3.33 (2H, m), 3.91 (2H, m), 7.05 (1H, dd, J =7, 1Hz), 7.12 (2H, d, J = 15.4Hz), 7.18 
(1H, dd, J = 8.8, 7Hz), 7.38-7.56 (12H, m), 7.61 (1H, d, J = 8.8Hz), 7.66 (1H, d, J = 1 .2Hz), 7.77 (1H, s) 

30 

(30) 5-[2-[2-(Acetylamino)-4-(methyl)-(5-thiazolyl)sulfonylamino]ethylthio]imidazo[1 ,2-a]pyridine (Compound 
51) 

NMR (200Hz, DMSO-d s ) 5: 2.17 (3H, s), 2.38 (3H, s), 3.07-3.49 (4H, m), 7.02 (1H, d, J = 7.2Hz), 7.23 (1H, 
35 dd, J = 8.8, 7.2Hz), 7.54 (1 H, d, J = 8.8Hz), 7.67 (1 H, s,), 7.90 (1 H, s), 8.20 (1 H, br) 

(31) 5-[3-(1-Naphthy!sulfony1amino)propylthio]imidazo[1 ,2-a]pyridine (Compound 52) Melting point: 140- 
141" C 

40 



Elemental analysis for C20H1 2 N3O2S2 , 


Calcd.: 
Found : 


C, 60.43; 
C, 60.58; 


H, 4.82; 
H, 4.85; 


N, 10.57 
N, 10.60 



(32) 5-[2-[N-Methyl-N-(1-naphthylsulfonylamino)]ethylthio]imidazo[1 ,2-a]pyridine hydrochloride (Compound 



Elemental analysis for C^cH-n^O-S 


z'HCl, 


Calcd : 


C 55.35: | H. 4.65: 


N 9.68 



EP 0 471 236 A1 



1Hz), 7.14 (1H, dd, J = 9, 7Hz), 7.45 (1H, dd, J = 8.4, 7.4Hz), 7.53-7.71 (5H, m), 7.90 (1 H, m), 8.02 (1H, d, 
J = 8.4Hz), 8.09 (1H, dd, J = 7.4, 1.2Hz), 8.60 (1H, m) 

(33) 5-[2-[N-Ethyl-N-(1-naphthylsulfonylamino)]ethylthio]imidazo[1 ,2-a]pyridine hydrochloride (Compound 
5 54) 

Melting point: 178-185° C 



70 


Elemental analysis for C21H21N3O2S 


2 * HCI, 




Calcd.: 


C, 56.30; 


H, 4.95; 


N, 9.38 




Found : 


C, 56.27; 


H, 4.97; 


N, 9.29 



75 NMR (200Hz, CDCI3) of the free compound 5: 1.06 (3H, t, J = 7.2Hz), 3.06 (2H, m), 3.30-3.50 (4H, m), 6.90 
1 (1H, d, J = 7.2Hz), 7.15 (1H, dd, J = 9, 7.2Hz), 7.41 (1H, m), 7.53-7.71 (5H, m), 7.86-8.10 (3H, m), 8.54 (1H, 
m) 

(34) 5-[2-[N-(2-Hydroxyethyl)-N-(1-naphthylsulfonylamino)]ethylthio]imidazo[1,2-a]pyridine hydrochloride 
2Q (Compound 55) 

Melting point: 172-1 76 *C 



Elemental analysis for C21 H 2 i N 3 0 3 S 2 • HCI, 


Calcd.: 
Found : 


C, 54.36; 
C, 54.74; 


H, 4.78; 
H, 4.85; 


N, 9.06 
N, 8.88 



NMR (200Hz, CDCI3) of the free compound 5: 2.10 (1H, br), 3.18 (2H, m), 3.41-3.62 (4H, m), 3.74 (2H, t, 
30 J = 5.2Hz) t 6.90 (1H, dd, J = 7, 1Hz), 7.12 (1H, dd, J = 9, 7Hz), 7.42 (1H, m), 7.85-8.10 (3H, m), 7.85-8.10 
(3H, m), 8.56 (1H, m) 

(35) 2-Methyl-5-[2-(1-naphthylsulfonylamino)ethylthio)imidazo[1 ,2-a]pyridine (Compound 56) 



Elemental analysis for C20H19N3O2S2, 


Calcd.: 
Found : 


C, 60.43; 
C, 60.24; 


H, 4.82; 
H, 4.84; 


N, 10.57 
N, 10.52 



NMR (200Hz, CDCI3) 5: 2 44 (3H, s), 2.89-3.11 (4H, m), 5.30 (1H, br), 6.47 (1H, dd, J = 7, 1.2Hz), 6.85 (1H, 
dd, J=9, 7Hz), 7.36-7.53 (3H, m), 7.96 (1H, dd, J = 6.8, 1.8Hz), 8.06 (1H, d, J = 8.2Hz), 8.19 (1H, dd, J = 7.4, 
1.2Hz), 8.63 (1H, d, J = 8.4Hz) 

(36) 3-Ethoxycarbonyl-2-methy1-5-[2-[1 -(naphthyl)sulfonylamino]ethylthio]imidazo[1 ,2-a]pyridine (Compound 
57) 



50 


Elemental analysis for C 2 3H 2 3N 3 04S 


2 '0.5H 2 O, 




Calcd.: 


C, 57.72; 


H, 5.05; 


N, 8.78 




Found : 


C, 57.85; 


H, 5.02; 


N, 8.63 



55 NMR (200Hz, CDCI3) 5: 1.41 (3H, t, J = 7.2Hz), 2.61 (3H, s), 2.95-3.05 (4H, m), 4.42 (2H, q, J = 7.2Hz), 5.29 
(1H, br), 6.82 (1H, dd, J = 7.2, 1Hz), 7.22 (1 H, dd, J = 9, 7.2Hz), 7.42-7.66 (4H, m), 7.91 (1H, m), 8.04 (1H, d, 
J = 8Hz), 8.16 (1H, dd, J = 7.4, 1.4Hz), 8.54 (1H, m) 



34 



BNISOOCIC <EP 0471236A1 J 



EP 0 471 236 A1 



(37) 2-Ethoxycarbonyl-5-[2-(1 -naphthylsulfonylamino)ethy lthio]imidazo[1 ,2-a]pyridine 
(Compound 58) 



5 


Elemental analysis for C22H21 N3CUS2, 




Calcd.: 


C, 58.00; 


H, 4.65; 


N, 9.22 




Found : 


C, 57.79; 


H, 4.63; 


N, 9.24 



NMR (200Hz, CDCh) 5: 1.45 (3H, t, J = 7.2Hz), 2.98 (2H, m), 3.12 (2H, m), 4.47 (2H, q, J = 7, 2Hz). 5.26 (1H, 
br), 6.65 (1H, dd, J = 7, 1Hz), 7.03 (1H, dd, J =9, 7Hz), 7.44-7.73 (4H, m), 7.95 (1H, dd, J = 7.8, 1.6Hz), 8.05 
(1H, d, J = 8.2Hz), 8.19 (1H, dd, J = 7.2, 1.2Hz), 8.24 (1H, s), 8.62 (1H, m) 

Example 1 1 

According to the same manner as that described in Example 4 (i), the (oiiuwiny uumpuund was 
obtained. 

3-Bromo-5-[2-(1 -(naphthyl)sulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 59) 





Elemental analysis for Ci9Hi&N 3 02S 2 Br, 


25 


Calcd.: 


C, 49.35; 


H, 3.49; 


N, 9.09 


Found : 


C, 49.39; 


H, 3.47; 


N, 8.98 



NMR (200Hz, CDCh) 5: 2.91 (2H, m), 3.10 (2H, m), 5.32 (1H, br), 6.51 (1H, dd, J = 7, 1Hz), 6.83 (1H, dd, 
J = 9, 7Hz), 7.43-7.73 (5H, m), 7.94 (1 H, dd, J = 7.8, 1.6Hz), 8.04 (1H, d, J = 8.2Hz), 8.19 (1H, dd, J =7.4, 
30 1 .2Hz), 8.64 (1 H, d, J = 8.2Hz) 

Example 12 

According to the same manner as that described in Example 3 (1), the following compounds were 
35 obtained. 

(1) 5-[2-(Methylsulfonylamino)ethyiamino]imidazo[1,2-a]pyridine (Compound 60) 

NMR (90Hz, CDCb-DMSO-ds) 5: 2.90 (3H. s). 3.44 (4H, m), 6.16 (1H, d, J = 7.5Hz), 6.99 (1H, d, J = 9Hz), 
40 7.28 (2H, br), 7.43 (1H, dd, J =9. 7.5Hz), 7.66 (1H, d, J = 1 .5Hz), 8.23 (1H, s) 

(2) 5-[3-(Methylsulfonylamino)propylamino]imidazo[1,2-a]pyndine (Compound 61) 

NMR (90Hz, CDCI 3 -DM60-d 6 ) 5: 1.97 (2H, m), 2.90 (3H, s), 3.17 (2H, m), 3.46 (2H, m), 6.19 (1H, d, J = 8Hz), 
45 6,91-7.20 (2H, m), 7.37-7.63 (2H, m), 7.71 (1H, d, J = 2Hz), 8.36 (1H, d, J = 2Hz) 

(3) 5-[2-(Methylsulfonylamino)ethyloxy]imidazo[1,2-a]pyridine (Compound 62) 



| Galea.. 


U. 


47.0b, 


H . 5.13, 


N. 


16.4b 


Found 


C, 


46.95; 


H, 5.17; 


N. 


16.38 



EP 0 471 236 A1 



NMR (200MHz, DMSO-d 6 ) 6: 3.71 (2H, m), 4.38 (2H, t, J = 5Hz), 6.38 (1H, dd, J = 6.6. 1.6Hz), 7.19-7.34 (2H, 
m), 7.60 (1H, s), 7.87 (1H, s) 

(5) 5-[3-(methyisulfonylammo)propyloxy]imidazo[1 ,2-a]pyridine (Compound 64) 

NMR (200Hz, CDCI 3 -DMSO-d 5 ) 6: 2.20 (2H, m), 2.93 (3H, s), 3.35 (2H, m), 4.39 (2H, t, J = 6.2Hz), 6.11 (1H, 
dd, J =6.8, 1.6Hz), 6.91 (1H, br), 7.14-7.29 (2H, m), 7.57 (1H, d, J = 1.4Hz), 7.67 (1H, m) 

(6) 5-[3-(Trifluoromethylsulfonylamino)propyloxy]imidazo[1 ,2-a]pyridine (Compound 65) 

NMR (200Hz, DMSO-d 6 ) 8: 2.05 (2H, m), 2.91 (3H, s), 3.21 (2H, m). 4.38 (2H, t. J = 6Hz), 6.35 (1H, dd, J = 7, 
1.2Hz), 7.10-7.32 (3H, m), 7.56 (1H, d, J = 1 4Hz), 7.78 (1H, s) 

(7) 5-[4-(methylsulfonylamino)butyloxy]imidazo[1 ,2-a]pyridine (Compound 66) 



Elemental analysis for Ci2Hi7N 3 03S, 


Calcd.: 
Found : 


C, 50.87; 
C, 50.60; 


H, 6.05; 
H, 6.11; 


N, 14.83 
N, 14.78 



NMR (200Hz, CDC 3 ) 5: 1.87 (2H, m), 2.04 (2H, m), 2.99 (3H, s), 3.28 (2H, m), 4.29 (2H, t, J = 6.2Hz), 4.58 
(1H, br), 6.04 (1H, d, J = 7.2Hz), 7.17 (1H, dd, J = 9, 7.2Hz), 7,29 (1H, d, J = 9Hz), 7.59 (1H, d, J = 1.4Hz), 
7.63 (1H, m) 

(8) 5-[4-(Trifluoromethylsulfonylamino)butyloxy]imidazo[1 ,2-a]pyridine (Compound 67) 



30 


Elemental analysis for C12H14N3 


O3SF3 




Calcd.: 


C, 42.73; 


H, 4.18; 


N, 12.56 




Found : 


C, 42.53; 


H, 4.27; 


N, 12.25 



35 NMR (200Hz, CDCl 3 -DMSO-d 6 ) 5: 1.87 (2H, m), 2.03 (2H, m), 3.30 (2H, m), 4.30 (2H, t, J = 6Hz), 6.08 (1H, 
dd, J = 6.4, 1.4Hz), 7.14-7.28 (2H, m), 7.57 (1H, s), 7.68 (1H, s) 

(9) 5-[5-(Methylsulfonylamino)pentyloxy]imidazo[1 ,2-a]pyridine (Compound 68) 



Elemental analysis for C13H19N3O3S 


Calcd.: 
Found : 


C, 52.51; 
C, 52.22; 


H, 6.44; 
H, 6.53; 


N, 14.13 
N, 13.83 



NMR (200Hz, CDCI 3 ) 5: 1.54-1.80 (4H, m), 1.97 (2H, m), 3.20 (2H, m), 4.25 (2H, t, J = 6.2Hz), 4.59 (1H, br), 
6.02 (1H, dd, J = 7.2, 1Hz), 7.17 (1H, dd, J = 9. 7Hz), 7.28 (1 H, d, J = 9Hz), 7.59(1 H, d, J = 1.4Hz), 7.63 (1H, 
m) 

(10) 5-[5-(Trifluoromethylsulfony!amino)pentyioxy]imidazo[1 ,2-a]pyridine (Compound 69) 



55 



Elemental analysis for Ci3HisN 3 


D 3 


SF 3 , 


Calcd.: 


C, 44.44; 


H, 4.59; 




N, 11.96 


Found : 


C, 44.47; 


H, 4.63; 




N, 11.71 



36 



3NSDOCU 



EP 0 471 236 A1 



NMR (200Hz, CDCI 3 ) 5: 1.63-2.02 (6H, m), 3.42 (2H, m), 4.18 (2H, t, J = 6Hz), 5.94 (1H, d, J = 7Hz), 7.12 (1H, 
dd, J=9, 7Hz), 7.23 (1H, d. J = 9Hz), 7.30 (1H, d, J = 1 Hz), 7.41 (1H, d, J = 1Hz) 

(11) 5-[6-(Methylsulfonylamtno)hexyloxy]imidazo[1,2-a]pyridine (Compound 70) 





Elemental analysis for Cm H21 N 3 O3S # 0.2H 2 O, 




Calcd.: 


C, 53.38; 


H, 6.85; 


N, 13.34 


70 


Found : 


C, 53.67; 


H. 7.04; 


N. 13.28 



NMR (200Hz, CDCb) 5: 1.40-1.73 (6H, m), 1.91 (2H, m), 3.17 (2H, m). 4.24 (2H, t, J = 6.2Hz), 4.61 (1H, br), 
6.02 (1H, dd, J=7, 1Hz), 7.17 (1H, dd, J = 9, 7Hz), 7.28 (1H, d, J = 9Hz), 7.59 (1H, d, J = 1.4Hz), 7.65 (1H, 
m) 

(1 2) 5-L6-(7ri[iuurorTi«iriyibuifofiyia(Tiiriu)iitJAyiuxy]ifni(JcizuLl ,2-ajpyriuintj (Compound 71 ) 

NMR (200Hz, CDCI3) 5: 1.32-2.03 (8H, m), 3.37 (2H, t, 6.6Hz), 4.17 (2H, t, J = 6.2Hz), 5.97 (1H, d, J = 7Hz), 
7.16 (1H, dd, J = 9, 7Hz), 7.21 (1H, br), 7.25 (1H, d, J = 9Hz), 7.51 (1H, d, J = 1.1Hz), 7.54 (1 H, s) 

(13) 5-[2-(Methylsulfonylamino)propyloxy]imidazo[1,2-a]pyridine (Compound 72) 
Melting point: 171-172* C 

(14) 5-[1-(Methylsulfonylamino)-(2-propyloxy)]imidazo[1 ,2-a]pyridine (Compound 73) 





Elemental analysis for C11H15N3O3S, 


30 


Calcd.: 


C, 49.06; 


H, 5.61; 


N, 15.60 




Found : 


C, 48.81; 


H, 5.63; 


N, 15.59 



NMR (200Hz, CDCI 3 ) 5: 1.47 (3H, d, J = 6.2 Hz), 3.01 (3H, s), 3.50 (2H, m), 4.84 (1H, m), 6.10 (1H, d, 
35 J = 7.4Hz), 6.38 (1H, br), 7.09 (1H, dd, J =9, 7.4Hz), 7.21 (1H, d, J=9Hz), 7.41 (1H, d, J = 1 .4Hz) 

(15) 5-[2-(Methylsulfonylamino)-1-(phenyl)ethyloxy]imidazo[1.2-a]pyridine (Compound 74) 

NMR (200Hz, CDCb) 6: 2.94 (3H. s), 3.61-3.83 (2H, m), 5.33 (1H, br), 5.58 (1H. dd, J = 7, 4.6Hz), 5.91 (1H, 
40 d, J = 7.4Hz), 7.00 (1H, dd, J=9, 7.4Hz). 7.24 (1H, d, J = 9Hz), 7.40 (5H, m), 7.60 (1H, d, J=1.4Hz), 7.73 
(1H, s) 

(16) 5-[[1-(Phenyl)-2-(trifluoromethylsulfonylamino)]ethyloxy]imidazo[1 ,2-a]pyridine 
(Compound 75) 

45 

NMR (200Hz, CDCI 3 -DMSO-d 6 ) 5: 3.49 (2H, m), 5.06 (1H, dd, J = 8, 4Hz), 5.98 (1H, d, J = 8.8Hz), 5.98 (1H, 
br), 7.04 (1H, d, J = 8.8Hz), 7.20-7.52 (6H, m), 7.60 (1H, s), 7.81 (1H, s) 



- /Hz;, A ' 1 1 M. QC o - -a. .'H*:/. / J ' 1 1M. , ^ - Umz i, /.bj (Iri. u. j - l.4H<:,. Abb [ ) ri s 
(18) 5-[1-(Trifuloromethy!sulfcnyl)-4-piperidyloxy]imidazo[1 ,2-a]pyndine (Compound 77) 



EP 0 471 236 A1 



(19) 5-[2-(1-(Naphthyl)sulfonylamino)ethyloxy]imidazo[1 ,2-a]pyridine (Compound 78) 



5 


Elemental analysis for CisHi/N 


3O3S, 




Calcd.: 


C, 62.11: 


H, 4.66; 


N, 1 1.44 




Found : 


C, 62.04; 


H, 4.57; 


N, 1 1.41 



NMR (200Hz, DMSO-d&) 6: 3.38 (2H, m), 4.11 (2H, t, J = 5.2Hz), 6.06 (1H, m), 7.08-7.20 (2H, m), 7.46-7.65 
(5H, m), 8.00 (1H, m), 8.16 (1H, s), 8.20 (1H, s). 8.47 (1H, br), 8.64 (1H, m) 

(20) 5-[3-(1-(Naphthyl)sulfonylamino)propyloxy]imidazo[1,2-a]pyridine (Compound 79) 



Elemental analysis for C2oHi 3 N 3 03S, 


Calcd.: 
Found : 


C, 62.97; 
C, 62.82; 


H, 5.02; 
H, 4.98; 


N, 11.02 
N, 11.14 



20 

NMR (200Hz, CDCb-DMSO-dO 5: 1.98 (2H, m), 3.19 (2H, m), 3.98 (2H, t, J=6Hz), 5.59 (1H, d, J = 7.2Hz), 
6.99-7.35 (4H, m), 7.43-7.63 (3H, m), 7.67-7.80 (3H, m), 8.14 (1H, d, J = 7.4Hz), 8.68 (1H, d, J = 8.2Hz) 

(21) 5-[6-(1-(Naphthyl)sulfonylamino)hexyloxy]imidazo[1,2-a]pyridine (Compound 80) 

25 





Elemental analysis for C 2 3H25N3O3S"0.3H 2 O, 




Calcd.: 


C, 64.40; 


H, 6.02; 


N, 9.80 


30 


Found : 


C, 64.66; 


H, 6.07; 


N, 9.68 



NMR (200Hz, CDCI3) 5: 1.10-1.83 (8H, m), 2.94 (2H, m) ( 4.12 (2H, t, J = 6.4Hz), 4.76 (1H, t, J = 6.6Hz), 5.98 
(1H, d, J=7Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.28 (1H, d, J = 9Hz), 7.50-7.72 (5H, m), 7.94 (1H, d, J=7.6Hz), 
8.07 (1 H, d, J = 8.4Hz), 8.28 (1 H, dd, J = 7.4, 1 2Hz), 8.66 (1 H, d, J = 8.8Hz) 

(22) 5-[2-(1-(Naphthyl)sulfonylamino)propyloxy]imidazo[1 ,2-a)pyridine (Compound 81) 
Melting point: 188-190* C 

(23) 5-t(l-(l-Naphthylsuifonyl))-(4-piperidy!)oxy]imidazo[1,2-a]pyridine (Compound 82) 

NMR (200Hz t CDCb) 6: 1.94-2.23 (4H, m), 3.29-3.53 (4H, m), 4.70 (1H ( m), 5.98 (1H, d, J = 7Hz), 7.12 (1H, 
dd, J =9, 7Hz), 7.25 (1H, d, J=9Hz), 7.39 (1H, s), 7.53 (1H, s), 7.53-7.73 (3H, m), 7.98 (1H, dd, J =7.2, 
2.2Hz), 8.13 (1H, d, J = 8.4Hz), 8.27 (1H, dd, J = 7.4, 1.2Hz), 8.75 (1H, dd, J = 7.8, 2.2Hz) 

Example 13 

(1) Synthesis of 5-[2-(acetylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 83) 

To a solution of 5-[2-(amino)ethylthio]imidazo[1 ,2-a]pyridine dihydrochloride (2.66 g, 10 mmoles) and 
triethylamine (4.32 ml, 31 mmoles) in N,N-dimethylformamide (24 ml) was added acetyl chloride (0.71 ml, 
10 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 4 hours. The 
reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed 
with saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the 
residue was purified by column chromatography (eluent: ethanol/ethyl acetate = 1:3) to obtain 1.57 g of the 
desired product (66.8%, colorless crystals). 



38 

BNSDOCID: <EP.__0471236A1_I_> 



EP 0 471 236 A1 



Elemental analysis for Ci 1 Hr 3N8OS'0.3H 2 O, 


Calcd.: 
Found : 


C, 54.89; 
C, 55.29; 


H, 5.69; 
H, 5.52; 


N, 17.46 
N, 17.42 



NMR (90MHz, CDCI 3 ) 5: 1.93 (3H, s), 3.13 (2H, m), 3.46 (2H, m), 6.98 (1H, dd, J = 7, 1 .5Hz), 7.07 (1H, or), 
7.13 (1H, dd, J = 8.5, 7Hz), 7.51 (1H, d, J = 85Hz), 7.65 (1H, s), 7.81 (1H, s) 

According to the same manner as that described in Examples 2 and 13 (1), the following compounds 
were obtained. 

(2) 5-[2-(Trifluoroacetylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 84) 

NMR (90MHz. DMSO-d 6 ) 5: 3.17-3.60 (4H, m), 7.12 (1H, dd, J = 7, 1.5Hz), 7.27 (1H, dd, J = 9, 7Hz), 7.58 
(1H, d, J = 9Hz), 7.67 (1H, d, J = 1.5Hz), 7.96 (1H, s), 9.60 (1H, br) 

(3) 5-[2-(Decanoy!amino)ethy!thio]imid3zo[1 ,2-3]pyridine (Compound 85) 

NMR (90MHz, CDCI 3 ) 5: 1.70-1.78 (17H, m), 2.15 (2H, m), 3.15 (2H, m), 3.49 (2H, m), 6.53 (1H, br), 7.00 
(dd, J = 7, 1.5Hz), 7.15 (1H, d, J = 9, 7Hz), 7.23 (1H, d, J = 9Hz), 7.67 (1H, s), 7.84 (1H, s) 

(4) 5-[2-(Aminoacetylamino)ethylthio]imidazo[1 ,2-a]pyridine dihydrochloride (compound 86) 

NMR (200MHz, DMSO-d 6 ) 5: 3.32-3.53 (4H, m), 3.55 (2H, s), 7.69 (1H, dd, J =6, 2.6Hz), 7.86-7.99 (2H, m) ( 
8.22 (1H, d, J = 2.2Hz), 8.26 (1H, d, J = 2.2Hz), 8.79 (1H, br) 

(5) 5-[2-(Benzoylamino)ethylthio]imidazo[1 ,2-a]pyridine(Compound 87) 

NMR (90MHz, CDCI3) 5: 3.27 (2H, m), 3.70 (2H, m), 6.74 (1H, br), 6.97-7.23 (2H, m), 7.30-7.95 (8H, m) 

(6) 5-[2-[3(2H)-Pyridazinone-6-carbonylamino]ethylthio]imidazo[1 ,2-a]pyridine 
(Compound 88) 

NMR (90MHz, DMSO-ds) 5:3.15-3.67 (4H, m), 6,93 (1H, d, J = 10Hz), 7.10-7.62 (3H, m), 7.66 (1H, s), 7.80 
(1H, d, J = 10Hz), 7.92 (1H, s), 8.64 (1H, br) 

(7) 5-[2-[(2-Thenoylamino)]ethylthio]imidazo[1,2-a]pyridine (Compound 89) 

NMR (200MHz, CDCI3) 6: 3.27 (2H, t, J = 6.4Hz), 3.68 (2H, m), 6.57 (1H, br), 7.02-7.20 (3H, m), 7.41-7.69 
(3H, m), 7.69 (1h, d, J = 1.2Hz), 7.85 (1H. s) 

(8) 5-[2-(1 -Naphthoyl)aminoethy!thio]imidazo[1 ,2-a)pyridine hydrochloride (Compound 90) 

NMR (200MHz, DMSO-d 6 ) 6: 3.50-3.75 (4H, m), 7.51-7.67 (4H, m), 7.75-8.07 (5H ( m), 8.22 (1H, m), 8.32 
(1H, d, J = 2.2Hz), 8.41 (1H, d, J = 2.2Hz), 8.85 (1H, br) 

NMR (200MHz, CDCI3) of the free amine 6: 3.30 (2H, t, J = 6.4Hz), 3.74 <2H, m), 6.68 (1H, br), 7.01-7.16 (2H, 
m), 7.36-7.58 (5H, m), 7.64 (1H, d, J = 1 .2Hz), 7.80-7.94 (3H, m), 8.29 (1H, m) 



(10) 5-[2-(Nicotinoy!amino)ethylthio]imiaazot 1 ,2-a]pyridine (Compound 92) 



EP 0 471 236 A1 



(11) 5-[2-(!sonicotinoyiamino)ethylthio]imidazo[1,2-a]pyridine (Compound 93) 

NMR (200MHz, CDCI 3 -DMSO-d & ) 5: 3.29 (2H, m), 3.68 (2H, m), 7.11 (1H, dd, J = 7, 1.4Hz), 7.19 (1H, dd, 
J = 8.8, 7.2Hz), 7.57 (1 H, d, J = 8.8Hz), 7.68 (2H, m), 7.88 (1 H, m), 8.23 (1 H, br), 8.72 (2H, m) 

5 

(12) 5-[2-[3,4-(Dimethoxy)phenylacetylamino]ethylthio]imidazo[1 ,2-a]pyridine' hydrochloride 
(Compound 94) 

Melting point: 150-165* C 

10 NMR (200MHz, CDCl 3 ) of the free amine &: 3.11 (2H, t, J = 6.6Hz), 3.43 (2H, m), 3.49 (2H, s), 3.85 (3H, s), 
3.87 (3H, s), 6.02 (1 H, br), 6.69-6.95 (4H, m), 7.12 (1H, dd, J = 9, 7Hz), 7.56 (1H, d, J = 9Hz), 7.66 (1H, s), 
7.74 (1H, S) 

(1 3) 5-[2-[3-(3-Pyridyl)acryloy!amino]ethylthio]imidazo[1 ,2-a]pyridine * dihydrochloride 
75 (Compound 95) 

NMR (200MHz, D 2 0) 5: 3.41 (2H, m), 3.61 (2H, m), 6.60 (1H, d, J = 16Hz), 7.36 (1H, d, J = 16Hz), 7.58-8.05 
(5H, m), 8.22 (1H, d, J = 2.6Hz), 8.59-8.72 (2H, m), 8.66 (1H, m) 

20 (14) 5-[3-(Benzoylamino)propylamino]imidazo[1,2-a]pyridine (Compound 96) 

NMR (90MHz, CDCI 3 -DMSO-de) 5: 1.99 (2H, m), 3.27-3.70 (4H, m), 5.86 (1 H, d, J = 7Hz), 6.25 (1H, br), 6.98 
(1H, d, J = 9Hz), 7.17 (1H, dd, J =9, 7Hz), 7.33-8.17 (8H, m) 

25 (15) 5-[3-(Decanoylamino)propylamino]imtdazo[1,2-a]pyridine (Compound 97) 

NMR (90MHz, CDCh) 6: 0.73-2.00 (19H, m), 2.22 (2H t m), 3.22-3.53 (4H, m), 5.77-6.03 (2H, m), 6.21 (1H, 
br), 6.95-7.22 (2H, m), 7.62 (1H, s), 7.71 (1H, s) 

30 Example 14 



(1) Synthesis of 5-[2-[2-(carboxy)benzoylamino]ethylthio]imidazo[1 ,2-a]pyridine (Compound 98) 

To a solution of 5-[2-(amino)ethylthio]imidazo[1 ,2-a]pyridine (1.12 g, 5.8 mmoles) in chloroform (58 ml) 
was added phthalic anhydride (1.12 g, 7.56 mmoles) and the mixture was stirred at room temperature for 14 
hours and then heated at reflux for 5 hours. The reaction mixture was cooled by standing. The crystals 
precipitated were filtered off, washed with chloroform and dried to obtain 1.68 g of the desired product 
(84.8%, colorless crystals). 

NMR (90MHz, DMSO-d 6 ) 5: 3.17-3.63 (4H, m). 7.15-7.91 (8H, m), 7.98 (1H, s), 8.21 (1H, br) 
Example 15 

(1) Synthesis of 5-[2-(phthalimide)ethylthio]imidazo[1 ,2-a]pyridine (Compound 99) 

To 5-[2-[2-(carboxy)benzoylamino]ethylthio]imidazo[1,2-a]pyridine dihydrochloride (638 mg, 2 mmoles) 
was added hydrogen chloride-methanol solution (40 ml) and the mixture was heated at reflux for 24 hours. 
After the solvent was distilled off, the residue was dissolved in chloroform, washed with an aqueous 
saturated sodium bicarbonate solution and dried over anhydrous magnesium sulfate. After the solvent was 
distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 530 mg of 
the desired product (81.9%, yellow crystals). 

NMR (90MHz, CDCI3) 6: 3.31 (2H, t, J = 7Hz), 3.95 (2H, t, J = 7Hz), 7.05-7.1 9 (2H, m), 7.42-7.92 (7H, m) 
Example 16 



55 (1) Synthesis of 5-[2-(methylcarbamoylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 100) 

To a solution of 5-[2-(amino)ethylthio]imidazo[1 ,2-a]pyridine (1.93 g, 10 mmoles) in methylene chloride 
(30 ml) was added methyl isocyanate (0.59 ml, 10 mmoles) under ice-cooling with stirring and the mixture 

40 

BNSDOCID: <EP 0471236A1 I 



EP 0 471 236 A1 



was stirred under ice-cooling for 1 hour. After the solvent was distilled off, the residue was purified by 
column chromatography (eluent: ethanol ethyl acetate = 1:5) to obtain 2.15 g of the desired product 
(86.0%, pale yellow crystals). 

NMR (90MHz, CDCI 3 ) 5: 2.74 (3H, d, J = 5.5Hz), 3.14 (2H, m), 3.43 (2H, m), 5.28 (1H, br), 5.76 (1H, br), 6.96 
5 (1H, dd, J = 7, 1Hz), 7.12 (1H, dd, J = 9, 7Hz), 7.51 (1H, d, J = 9Hz), 7.65 (1H, s), 7.79 (1H, s) 

According to the same manner as that described in Example 16 (1), the following compounds were 
obtained. 

(2) 5-[2-(Ethylcarbamoylamino)ethy!thio]imidazo[1 ,2-a]pyridine (Compound 101) 

70 

NMR (200MHz, CDCI 3 ) 5:1.11 (3H, t, J = 7.2Hz), 3.16 (4H, m), 3.44 (2H, m), 4.72 (1H, br). 5.16 (1H, br), 6.97 
(1H, dd, J = 7, 1Hz), 7.14 (1H, dd, J = 9, 7Hz). 7.53 (1H, d, J = 9Hz), 7.66 (1H, d, J = 1.2Hz), 7.78 (1H, s) 

(3) 5-[2-(Propylcarbamoylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 102) 

75 

NMR (200MHz, CDCh) 5:0.90 (3H, t, J = 7.4Hz), 1.49 (2H, m), 3.03-3.22 (4H, m), 3.45 (2H, m), 4.68 (1H, br), 
5.07 (1H, br), 6.98 (1H, dd, J = 7, 1Hz). 7.15 (1H, d, J=9, 7Hz), 7.54 (1H, d, J = 9Hz), 7.67 (1H, d, J = 1.2Hz), 
7.80 (1H, s) 

20 (4) 5-[2-(lsopropylcarbamoylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 103) 

NMR (200MHz, CDCI3) 5:1.22 (6H, t, J = 6.6Hz), 3.17 (2H, t, J = 6.4Hz), 3.44 (2H, m), 3.84 (1H, hep- 
tet,J = 6.4Hz), 4.44 (1H, br), 4.96 (1H, br), 6.98 (1H, d, J = 7Hz). 7.15 (1H, dd, J =9, 7Hz), 7.55 (1H, d, 
J = 9Hz), 7.68 (1H, d, J = 1.2Hz), 7.80 (1H, s) 

25 

(5) S-^-fButylcarbamoylaminoJethylthiolimidazofl^-alpyridine (Compound 104) 

NMR (200MHz, CDCI3) 5:0.89 (3H, t, J=7Hz), 1.20-1.52 (4H, m), 3.07-3.20 (4H, m), 3.43 (2H, m), 5.23 (1H, 
br), 5.68 (1H, br), 6.95 (1H, dd, J = 7, 1Hz). 7.12 (1H, dd, J = 9, 7Hz), 7.49 (1H, d, J=9Hz), 7.63 (1H, d, 
30 J = 1.2Hz), 7.75 (1H, s) 

(6) 5-[2-(Cyclohexylcarbamoylamino)ethylthio]imidazo[1,2-a]pyridine (Compound 105) 

NMR (200MHz, CDCI3) 5:0.95-1.97 (10H, m), 3.17 (2H, t, J = 6.4Hz), 3.35-3.55 (3H, m), 4.48 (1H, br), 4.93 
35 (1H, br), 6.99 (1H, d, J = 7.2Hz), 7.16 (1H, dd, J = 9, 7.2Hz). 7.55 (1H, d, J = 9Hz), 7.68 (1H, s), 7.80 (1H, s) 

(7) 5-[2-(Phenylcarbamoylamino)ethylthio]imidazo[1,2-a]pyridine (Compound 106) 

NMR (200MHz, CDCh-DMSO-dO 5:3.19 (2H, m), 3.46 (2H, m), 6.25 (1H, br), 6.83-7.63 (8H, m). 7.69 (1H, s), 
40 7.88 (1H, s), 8.14 (1H, br) 

Example 17 

(1) Synthesis of 5-[2-(methylthiocarbamoylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 107) 

45 

To a solution of 5-[2-(amino)ethylthio]imidazo[1 ,2-a]pyridine (2.96 g, 15.3 mmoles) in methylene 
chloride (50 ml) was added methyl isocyanate (1.12 ml, 15.3 mmoles) under ice-cooling with stirring and the 

mixture was stirred at mom temperature for 3 hours After the ^nlven* was ronrentrated ether was added 



Elemental analysis for C- • H- * 


N*S 2l 


Calcd.: 


C. 49.60; 


H, 5.30, 


N, 21.03 




r 49 R Q 


H 5 


N ?<■ 



EP 0 471 236 A1 



According to the same manner as that described in Example 17 (1), the following compounds were 
obtained. 

(2) 5-[2-(Phenylthiocarbamoylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 108) 

5 

NMR (200MHz, CDCh) 5:3.31 (2H, m), 3.86 (2H, m), 6.44 (1H, br), 6.96 (1H, dd, J=7, 1.5Hz), 7.03-7.64 (7H, 
m), 7.67 (1 H, dd, J = 7, 1 .5Hz), 7.77 (1 H, s), 8.05 (1 H, br) 

(3) 5-[2-[4-(Methoxy)phenylthiocarbamoylamino]ethylthio]imidazo[1 ,2-a]pyridine (Compound 109) 

70 

NMR (200MHz, CDCb-DMSO-de) 5:3.32 (2H, m), 3.79 (2H, m), 3.82 (2H, m), 6.78-7.58 (1H, d, J = 7, 2Hz), 
7.64 (1H, d, J=2Hz), 7.85 (1H, d, J = 2Hz), 9.21 (1H, br) 

(4) 5-[2-[4-(Methyl)phenylthiocarbamoylamino]ethylthio]imidazo[1,2-a]pyridine (Compound 110) 

NMR (200MHz, CDCI 3 -DMSO-d&) 6:2.34 (3H t s), 3.32 (2H, m), 3.86 (2H, m), 7.05-7.33 (7H, m), 7.55 (1H, d, 
J = 9Hz), 7.68 (1 H, s), 7.85 (1 H, s), 8.98 (1 H, br) 

(5) 5-[2-[4-(Chloro)phenylthiocarbamoylamino]ethylthio]imidazo[1 ,2-a]pyridine (Compound 111) 

20 

NMR (200MHz, CDCI 3 -DMSO-d 6 ) 5:3.34 (2H, m), 3.86 (2H, m), 7.05-7.75 (9H, m), 7.88 (1H, s), 9.36 (1H, br) 

(6) 5-[2-[(1-Naphthyl)thiocarbamoylamino]ethylthio]imidazo[1 ,2-a]pyridine (Compound 112) 

25 NMR (200MHz, CDCI 3 -DMSO-d 6 ) 5:3.32 (2H, m), 3.80 (2H, m), 7.07-7.23 (2H, m), 7.37-8.08 (11H, m), 9.65 
(1H, br) 

(7) 2-Ethoxycarbonylmethyl-5-[2-(phenylthiocarbamoylamino)ethylthio]imidazo]1 ,2-a]pyridine (Compound 
113) 

30 

NMR (200MHz, CDCI 3 ) 5:1.30 (3H, t f J=7Hz), 3.23 (2H, t, J = 6.4Hz), 3.85 (2H, m), 3.88 (2H, s), 4.22 (2H,q, 
J = 7Hz), 6.31 (1H, br), 6.94 (1H, dd, J = 7, 1Hz). 7.11 (1H, dd, J = 9, 7Hz), 7.13-7.53 (6H, m), 7.69 (1H, br), 
7.79 (1H, s) 

35 (8) 2-Ethoxycarbonyl-5-[2-(phenylthiocarbamoylamino)ethylthio]imidazo[1,2-a]pyridine (Compound 114) 

NMR (200MHz, CDCh) 6:1.46 (3H, t, J=7.2Hz), 3.38 (2H, t, J = 6.6Hz), 3.94 (2H, m), 4.71 (2H, q, J = 7.2Hz), 
6.62 (1H, br), 7.07 (1H, dd, J = 7, 1.2Hz), 7.16-7.54 (7H, m), 7.91 (1H, br), 8.83 (1H, s) 

AO (9) 2-Methyl-5-[2-(phenylthiocarbamoylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 1115 

NMR (200MHz, CDCI3) 5:2.47 (3H, s), 3.31 (2H, t, J = 6.4Hz), 3.85 (2H, m), 6.38 (1H, br), 6.88 (1H, dd, J = 7, 
1Hz), 7.07 (1H, dd, J =9, 7Hz). 7.15-7.52 (7H, m), 7.82 (1 H t br) 

45 (10) 3-Ethoxycarbonyl-2-methyl-5-[2-(phenylthiocarbamoylamino)ethylthio]imidazo[1 ,2-a]pyridine 

(Compound 116) 

NMR (200MHz, CDCI 3 ) 5:1.37 (3H, t, J = 7Hz), 2.58 (3H, s), 3.33 (2H, t, J = 6Hz), 3.76 (2H, m), 4.35 (2H, q, 
J = 7Hz), 3.76 (2H, m), 4.35 (2H, q, J=7Hz), 6.47 (1H, br), 6.99-7.57 (8H, m), 7.76 (1H, br) 

50 

(11) 5-[3-(Phenylthiocarbamoylamino)propylthio]imidazo[1 ,2-a]pyridine (Compound 117) 

NMR (200MHz, CDCI 3 ) 5:1.96 (2H, m), 3.01 (2H, t, J = 7Hz), 3.79 (2H, m), 6.13 (1H, br), 6.87 (1H, d, 
J = 7Hz), 7.00-7.70 (8H, m), 7.88 (1H, s), 7.85 (1H, br) 

55 

Example 18 

(1) Synthesis of 5-[2-(methylcarbamoyloxy)ethylthio]imidazo[1 ,2-a]pyridine (Compound 118) 

42 

3NSDOCID. <EP _C471236A1.a > 



EP 0 471 236 A1 

To a solution of 5-[2-(hydroxy)ethylthio]imidazo[1 ,2-a]pyridine (971 mg, 5 mmoles) and triethylamine 
(0.91 ml, 6.53 mmoles) in methylene chloride (40 ml) was added methyl isocyanate (0.65 ml, 11 mmoles) 
under ice-cooling with stirring and the mixture was stirred at room temperature for 12 hours. The reaction 
mixture was washed with saturated saline and dried over anhydrous magnesium sulfate . After the solvent 
5 was distilled off, the residue was purified by column chromatography (eluent: methanol/chloroform = 1:20) 
to obtain 1.07 g of the desired product (85.2%, colorless crystals). 

NMR (200MHz, CDCI 3 ) 5: 2.74 (3H, d, J = 4.8Hz). 3.21 (2H, t, J = 6.2Hz), 4.27 (2H, t, J = 6.2Hz), 4.56 (1H, br), 
7.05 (1H, dd, J = 9, 7Hz), 7.21 (1H, dd, J = 9, 7Hz), 7.61 (1H, d, J = 9Hz), 7.71 (1H, s), 7.89 (1 H, s) 

According to the same manner as that described in Example 18 (1), the following compounds were 
70 obtained. 

(2) 5-[2-(Butylcarbamoyloxy)ethylthio]imidazo[1 ,2-a]pyridine (Compound 119) 

NMR (200MHz, CDCI 3 ) 6:0.92 (3H, t, J = 7Hz), 1.21-1.55 (4H, m), 3.03-3.30 (4H, m), 4.26 (2H, t, J = 6.4Hz), 
75 4.55 (1H, br), 7.05 (1H, d. J = 7Hz), 7.17 (1H, dd, J = 9, 7Hz). 7.62 (1H, d, J=9Hz), 7.72 (1 H, s), 7.89 (1H, s) 

(3) 5-(2-(Phenylcarbamoyloxy)ethylthio]imidazo[1 ,2-aJpyridine (Compound 120) 

NMR (200MHz, DMSO-d 6 ) 5:3.45 (2H, t, J = 6.2Hz), 4.32 (2H, t, J=6.2Hz), 7.00 (1H, m), 7.16 (1H, dd, J = 7, 
20 1Hz), 7.22-7.34 (3H, m), 7.42-7.50 (2H, m), 7.57 (1H, d, J = 9Hz), 7.70 (1H, d, J = 9Hz), 7.70 (1H, d, 
J = 1 .2Hz), 7.99 (1 H, s), 9.74 (1 H, br) 

(4) 5-[2-[(1-Naphthyl)carbamoyloxy]ethylthio]imidazo[1,2-a]pyridine (Compound 121) 

25 NMR (200MHz, CDCI 3 -DMSO-d 6 ) 6:3.30 (2H, t, J = 6.4Hz), 4.41 (2H, t, J = 6.4Hz), 7.05-7.21 (2H, m), 7.41- 
7.75 (7H, m), 7.82-8.02 (3H, m), 8.11 (1H, br) 

(5) 5-[2-(Benzylcarbamoyloxy)ethylthio]imidazo[1 ,2-a]pyridine (Compound 122) 

30 NMR (200MHz, CDCI 3 ) 6:3.21 (2H, t, J = 6.4Hz), 4.24-4.37 (4H, m), 4.99 (1H, br), 7.24 (1H, d, J = 7Hz), 7.13 
(1H, dd, J =9, 7Hz), 7.24 (1H, d, J = 7Hz). 7.20-7.39 (5H, m), 7.58 (1H, dd, J = 9, 0.8Hz), 7.68 (1H, d, 
J = 1.2Hz), 7.87 (1H, s) 

Example 19 

35 

(1) Synthesis of 5-[2-[3-(hydroxy)propylcarbamoyloxy]ethylthio]imidazo[1 ,2-a]pyridine (Compound 123) 

To 5-[2-(phenoxycarbonyloxy)ethylthio]imidazo[1 ,2-a]pyridine (1.10 g, 3.50 mmoles) was added 3- 
aminopropanol (0.27 ml, 3.52 mmoles) and the mixture was stirred at 120* C for 1.5 hours. The reaction 
40 mixture was cooled by standing and chloroform was added thereto, which was washed with water and dried 
over anhydrous magnesium sulfate, and then the solvent was distilled off. Then, the residue was purified by 
column chromatography (eluent: methanol/chloroform = 1:20) to obtain 575 mg of the desired product 
(55.6%, colorless crystals). 



Elemental analysis for Ci 3H1 7N3O3S '0.2^0, 


Calcd.: 

r f-h 


C, 52.23; 


H, 5.87; 

M q TP- 


N, 14.06 

N 1 4 PR 



d, J = 1.4Hz), 7.90 (1H, s, 

According to the same manner as that described in Example 19 (1), the following compounds were 

r:h)+Ti j rod 



EP 0 471 236 A1 



Elemental analysis for H 23 N 3 0 3 S *0.2H 2 O, 


Calcd.: 
Found : 


C, 56.35. 
C, 56.63. 


H, 6.92; 
H, 6.89; 


N, 12.32 
N, 12.43 



NMR (200MHz, CDCl 3 ) 5:1.22-1.65 (8H, m), 2.16 (1H, br), 3.10 (2H, m), 3.21 (2H, t, J = 6.2Hz), 3.64 (2H, t, 
J = 6.2Hz), 4.26 (2H, t, J = 6.2Hz). 4.48 (1H, br), 7.05 (1H, dd, J = 7, 1.2Hz), 7.17 (1H, dd, J = 8.8, 7Hz), 7.60 
(1 H, m), 7.70 (1 H, d, J = 1 4Hz), 7.89 (1 H, m) 

(3) 5-[2-[3-(Morpholino)propylcarbamoyloxy]ethylthio]imidazo[1 ,2-a]pyridine (Compound 125) 

NMR (200MHz, CDCI 3 ) 6:1.66 (2H, m). 2.35-2.48 (6H, m), 3.16-3.30 (4H, m), 3.65-3.75 (4H, m), 4.26 (2H, t, 
J = 6.4Hz), 5.77 (1H, br), 7.05 (1H. dd, J = 7, 1Hz). 7.17 (1H, dd, J=9, 7Hz), 7.61 (1H, d, J = 9Hz), 7.72 (1H, 
d, J = 1.2Hz), 7.89 (1H, s) 

(4) 5-[2-[3-(1-lmidazolyl)propylcarbamoyloxy]ethylthio]imidazo[1 ,2-a]pyridine (Compound 126) 

NMR (200MHz, CDCI3) 6:1.96 (2H, q, J = 6.8Hz), 3.06-3.27 (4H, m), 3.97 (2H, t, J = 6.8Hz), 4.27 (2H, t, 
J = 6.2Hz), 5.06 (1 H, br), 6.93 (1 H, s), 7.05 (1 H, d, J = 7Hz). 7.07 (1 H, s), 7.1 7 (1 H, m), 7.48 (1 H, s), 7.61 (1 H, 
dd, J = 9, 0.8Hz), 7.71 (1 H, s), 7.89 (1 H, s) 

(5) 5-[2-[4-(Pyridyl)methylcarbamoyloxy]ethylthio]imidazo[1 ,2-a]pyridine (Compound 127) 

NMR (200MHz, CDCI 3 ) 6:3.23 (2H, t, J = 6.2Hz), 4.25-4.40 (4H, m), 5.36 (1H, br), 7.05 (1H, d, J=7Hz), 7.10- 
7.20 (2H, m), 7.60 (1 H, d, J = 9Hz), 7.70 (1 H, d, J = 1 Hz). 7.90 (1 H, s), 7.90 (1 H, s), 8.56 (2H, m) 

Example 20 

(1) Synthesis of 5-[2-(methoxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 128) 

To a solution of 5-[2-(amino)ethylthio]imidazo[1 ,2-a]pyridine (1.93 g, 10 mmoles) and triethylamine (1.53 
ml, 11 mmoles) in methylene chloride (30 ml) was added methyl chloroformate (0.77 ml, 10 mmoles) under 
ice-cooling with stirring and the mixture was stirred at room temperature for 20 minutes. The reaction 
mixture was washed in turn with an aqueous sodium bicarbonate solution and water, dried over anhydrous 
magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatog- 
raphy (eluent: ethanol/ethyl acetate = 1:10) to obtain 1.68 g of the desired product (66.9%, colorless 
crystals). 

Melting point: 198.0-200.0* C 



Elemental analysis for C1 1 Hi 3N 3 02S, 


Calcd.: 
Found : 


C, 52.57, 
C, 52.68, 


H, 5.21; 
H, 5.22; 


N, 16.72 
N, 16.60 



NMR (200MHz, CDCI3) 5:3.12 (2H, m), 3.40 (2H, m) t 3.68 (3H, s), 5.10 (1H, br), 7.00 (1H, d, J=7Hz), 7.16 
(1 H, dd, J = 9, 7Hz). 7.61 (1 H, d, J = 9Hz). 7.72 (1 H, s), 7.87 (1 H, s) 

According to the same manner as that described in Examples 2 and 20 (1), the following compounds 
were obtained. 

(2) 5-[2-(Ethoxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 129) 
Melting point: 68-70* C 



44 



EP 0 471 236 A1 



Elemental analysis for C^H^NsC^S, 


Calcd.: 
Found : 


C, 54.32; 
C, 54.43; 


H, 5.70; 
H, 5.75; 


N, 15.84 
N, 15.83 



(3) 5-[2-(Propyloxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine (Compound 130) 
Melting point: 62-64* C 





Elemental analysis for Ci 3H1 7N3O2S, 




Calcd.: 


C, 55.89; 


H, 6.13; 


N, 15.04 


75 


Found : 


C, 55.87; 


H, 6.09; 


N, 14.96 



NMR (200MHz, CDCI 3 ) 5:0.92 (3H, t, J = 7.4Hz), 1.62 (2H, m), 3.14 (2H, t, J = 6.6Hz), 3.42 (1H, m), 4.01 (1H, 
t, J=6.6Hz), 5.07 (1H, br), 7.02 (1H, d, J = 7Hz). 7.17 (1H, dd, J = 9, 7Hz), 7.60 (1H, d, J = 9Hz), 7.71 (1H, d, 
J = 1.2Hz), 7.86 (1H, s) 
20 IR (KBr) cm" 1 : 3210, 3025, 2965, 1695, 1620, 1545, 1490, 1275 

(4) 5-[2-(Butyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 131) 

Melting point: 75-76* C 



Elemental analysis for C14H19N3O2S, 


Calcd.: 
Found : 


C, 57.31; 
C, 57.32; 


H, 6.53; 
H, 6.55; 


N, 14.32 
N, 14.23 



NMR (200MHz, CDCI 3 ) 5:0.93 (3H, t, J = 7Hz), 1.35 (2H, m), 1.58 (2H, m), 3.14 (2H, t, J = 6.4Hz), 3.41 (2H, 
m), 4.05 (2H, t, J = 6.6Hz), 5.04 (1H, br), 7.16 (1H, dd, J=9, 7Hz), 7.60 (1H, d, J = 9Hz), 7.71 (1H, d, 
J = 1.2Hz), 7.85 (1H, s) 

IR (KBr) cm" 1 : 3490, 3210, 2970, 1695, 1615, 1500, 1285 

(5) 5-[2-(lsopropyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyndine (Compound 132) 
Melting point: 80.0-81 .0'C 



Elemental analysis for CisH^NaC^S, 


Calcd.: 
Found . 


C, 55.89; 
C, 55.85; 


H, 6.13; 
H, 6.14, 


N, 15.04 
N, 14.96 



NMR (200MHz, CDCI3) 5:1.22 (6H, t, J = 6.2Hz), 3.14 (2H, t, J = 6.4Hz), 3.41 (2H, m), 4.94 (1H, br), 7.02 (1H, 
d, J = 7Hz), 7.17 (1H, dd, J = 9, 7Hz), 7.61 (1H, d, J = 9Hz), 7.71 (1H, d, J = 1.4Hz), 7.86 (1H, s) 



Melting point: 145-150* C 

(7) 5-[2-(lsobutyloxycarbony!amino)ethylthio]imidazo[1 .2-a]pyridine (Compound 134) 



EP 0 471 236 A1 



Elemental analysis for Ci4Hi S N 3 0 2 S, 


Calcd.: 
Found : 


C, 57.31; 
C, 57.29; 


H, 6.53; 
H, 6.53; 


N, 14.32 
N, 14.41 



NMR (200MHz, CDCI 3 ) 5:0.91 (6H, d. J = 6.8Hz) ( 1.89 (1H, m), 3.14 (2H, t, J = 6.4Hz), 3.42 (2H m) 3 84 (2H 
d, J = 6.6Hz), 5.15 (1H, br), 7.01 (1H, d, J = 7Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.59 (1H, d J = 9Hz) 770 MM d' 
J= 1.2Hz), 7.85 (1H, s) ' ' ' ' 

(8) 5-[2-(Allyloxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine (Compound 135) 
Melting point: 72.5-73.5* C 



75 


Elemental analysis for Ci3Hi5N 3 02S, 




Calcd.. 


C, 56.30; 


H, 5.45; 


N, 15.15 




Found : 


C, 56.34; 


H, 5.44; 


N, 15.04 



20 NMR (200MHz, CDCI 3 ) 5:3.15 (2H, t, J = 6.4Hz), 3.43 (2H, m), 4.56 (2H, m), 5.07 (1H, br) 5 18-5 36 (2H m) 
5.90 (1H, m). 7.02 (1H, d, J=7Hz) t 7.17 (1H, dd, J = 9, 7Hz), 7.61 (1H, d, J = 9Hz), 7 72 (1 H d J = 1 4Hz)' 
7.86 (1H,m) ' ' " 

IR (KBr) cm 3205, 3020, 1700, 1625, 1570, 1490, 1270 

25 (9) 5-[2-f2,2,2-(Trichloro)ethoxycarbonylamino]ethylthio]imidazo[1,2-a]pyridine (Compound 136) 
Melting point: 11 3-11 4.0 *C 



30 


Elemental analysis for C12H1 2N 3 0 2 SCI 3t 




Calcd.: 


C, 39.10; 


H, 3.28; 


N, 11.40 




Found : 


C, 39.23; 


H, 3.27; 


N, 11.25 



NMR (200MHz, CDCI 3 ) 5:3.17 (2H, t, J = 6.4Hz), 3.48 (2H, m), 4.73 (2H, s), 5.52 (1H, br) 7 03 (1H d 
J = 7Hz), 7.1 7 (1 H, dd, J = 9, 7Hz), 7.62 (1 H, d, J = 9Hz), 7.71 (1 H, d, J = 1 .2Hz), 7.87 (1 H, m) 
IR (KBr) cm" 1 : 3195, 2975, 1725, 1615, 1545, 1485, 1260, 1210 

(10) 5-[2-(Benzyloxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine (Compound 137) 
Melting point: 52-53* C 





Elemental analysis for Ci7Hi7N 3 02S, 


45 


Calcd.: 


C, 62.36; 


H, 5.23; 


N, 12.83 




Found : 


C, 62.34; 


H, 5.22; 


N, 12.75 



NMR (200MHz, CDCI 3 ) 5:3.14 (2H, t, J = 6.4Hz), 3.43 (2H, m), 5.09 (2H, s), 5.17 (1H, br), 6 99 (1H d 
J = 6.8Hz), 7.1 3 (1 H, dd, J = 9.2, 6.8Hz), 7.35 (5H, s), 7.59 (1 H, d, J = 9.2Hz), 7.69 (1 H, s), 7.84 (1 H, s) 

(11) 5-[2-[(9-Fluorenyl)methyloxycarbonylamino]ethylthio]imidazo[1,2-a]pyridine (Compound 138) 
Melting point: 105.0-108.0* C 



BNSDOCIC: <EP 0471236A1 I > 



46 



EP 0 471 236 A1 



Elemental analysis for C 25 H 2 i N 3 O 2 S*0.4H 2 O, 


Calcd.: 
Found : 


C, 69.07; 
C, 69.14; 


H, 5.05; 
H, 5.23; 


N, 9.67 
N, 9.96 



NMR (200MHz, CDCI 3 ) 6:3.13 (2H, t. J = 6Hz), 3.42 (2H, m), 4.21 (1H, t, J = 6.6Hz), 4.43 (2H, d, J = 6.6Hz), 
5.17 (1H, br), 7.01 (1H, d, J = 7.4Hz), 7.15 (1H, dd, J = 8.6, 7.4Hz), 7.29-7.46 (4H, m), 7.53-7.65 (3H, m), 
7.60-7.87 (4H, m) 

!R (KBr) cm' 1 : 3205, 3020, 1710, 1625, 1550, 1485, 1450, 1270 

(12) 5-[2-(Phenoxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 139) 

Melting point: 96.0-97.0 "C 



Elemental for CigH^^C^S, 


Calcd.; 
Found : 


C. 61.32; 
C, 61.35; 


H, 4.82; 
H, 4.86; 


N, 13.41 
N, 13.30 



20 

IR (KBr) cm" 1 . 3200, 3005, 1725, 1615, 1555. 1485, 1270, 1210 

(1 3) 5-[2-(N-Methyl-N-isopropyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 1 40) 

25 NMR (200MHz, CDCI3) «: 1.02-1.35 (6H, m), 2.91 (3H, s), 3.05-3.26 (2H, m), 3.38-3.60 (2H, m), 4.89 (1H, m), 
7.01 (1H, br), 7.18 (1H, dd, J = 9, 7Hz), 7.60 (1H, d, J = 9Hz), 7.71 (1H, s), 7.84 (1H, s) 
IR (KBr) cm" 1 3220, 3025, 2970, 1705, 1630, 1545 

(14) 5-[2-(N-Ethyl-N-isopropyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 141) 

30 

NMR (200MHz, CDCI3) 5: 0.95-1.35 (9H, m), 3.02-3.68 (6H, m), 4.90 <1H, m), 7.04 (1H, m), 7.19 (1H, dd, 
J = 9, 7Hz), 7.60 (1 H, d, J = 9Hz), 7.72 (1 H, s), 7.83 (1 H, s) 
IR (KBr) cm- 1 3220, 3025, 2970, 1705, 1630, 1545 

35 Example 21 

(1) According to the same manner as that described in Example 4 (1), the following compounds were 
obtained. 

40 3-Bromo-5-[2-(isopropyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 142) 
Melting point: 1 03.0-104.0 ' C 



45 


Elemental analysis for Ci3Hi 6 N 3 0 2 SBr, 




Calcd.: 


C, 43.58; 


H, 4.50; 


N, 11.73 




Found : 


C, 43.60; 


H, 4.53; 


N, 11.74 



(2) 3-Chloro-5-[2-(isopropyloxycarbonylamino)ethylthio]imidazo[l ,2-a]pyndine (Compound 143) 



EP 0 471 236 A1 



Elemental for Ci 3 Hi 6 N 3 O 2 SCI*0.2H 2 O, 


Calcd.: 
Found : 


C, 49.19; 
C, 49.38; 


H, 5.21; 
H, 5.26; 


N, 13.24 
N, 13.22 



NMR (200MHz, CDCI3) 5: 1.22 (6H, d, J = 6.4Hz), 3.12 (2H, t, J = 6.4Hz), 3.43 (2H, m), 4.90 (1H, heptet 
J = 6.4Hz), 4.96 (1H, br), 6.99 (1H, dd, J = 7.2, 1.2Hz), 7.10 (1H, dd, J = 8.8, 7.2Hz), 7.53 (1H, dd' J = 88 
1.2Hz), 7.54 (1H, s) 

Example 22 

According to the same manner as that described in Example 5, the following compound was obtained. 
5-[2-(lsopropyloxycarbony lamino)ethylthio]-3-(morpholinomethyl)imidazo[1 ,2-a]pyridine (Compound 1 44) 

NMR (200MHz, CDCI3) 5: 0.96 (6H, d, J = 6.2Hz), 2.56 (4H, m), 3.26 (2H, m), 3.36 (2H, m), 3.65 (4H, m), 
4.10 (2H, s), 4.59 (1H, heptet, J = 6.2Hz), 6.85 (1H, br), 7.01 (1H, d, J = 5Hz), 7.13 (1H, dd, J = 8.6, 6.6Hz) 
7.51 (1H, s), 7.53 (1H, d, J = 8.6Hz) 

Example 23 

(1) According to the same manner as that described in Example 20 (1), the following compounds were 
obtained. 

5-[3-(Methoxycarbonylamino)propylthio]imidazo[1 ,2-a]pyridine (Compound 1 45) 
Melting point: 69.0-70.0 "C 



30 


Elemental analysis for Ci2H 15 N302S, 




Calcd.: 


C, 54.32; 


H, 5.70; 


N, 15.84 




Found : 


C, 54.48; 


H, 5.74; 


N, 15.72 



NMR (200MHz, CDCI3) 5: 1.85 (2H, m), 3.02 (2H, t, J = 7Hz), 3.32 <2H, m), 3.67 (3H. s), 4.85 (1H, br), 6.91 
(1H, dd, J = 7, 1.2Hz), 7.15 (1H, dd, J=9, 7Hz), 7.58 (1H, d, J = 9Hz), 7.70 (1H, d, J = 1.2Hz), 7.84 (1 H, s) 

(2) 5-[3-(lsopropyloxycarbonylamino)propylthio]imidazo[1,2-a]pyridine (Compound 146) 

NMR (200MHz, CDCI 3 ) 5: 1.22 (6H, d, J = 6.2Hz), 1.85 (2H, m), 3.03 (2H, m), 3.31 (2H, m), 4.82 (1H, br), 
4.90 (1H, heptet, J = 6.2Hz), 6.90 (1H, dd, J = 7, 1Hz), 7.15 (1H, dd, J = 9. 7Hz), 7.57 (1H, m), 7.69 (1H d 
J = 1.4Hz), 7.84 (1H, m) 

IR (KBr) cm- 1 : 3210, 3025, 2965, 1695, 1620, 1545, 1490, 1275 

(3) 5-[1-(tert-Butoxycarbonyl)-4-piperidylthio]imidazo[1,2-a]pyridine (Compound 147) 

NMR (200MHz, CDCI 3 ) 5:1.45 (9H, s), 1.50-1.98 (4H, m), 2.90 (2H, m), 3.36 (1H, m), 3.98 (2H, m), 7.03 (1H, 
dd, J = 7, 1.2Hz), 7.15 (1H, dd, J = 9, 7Hz), 7.64 (1H, m), 7.70 (1H, d, J = 1.2Hz), 7.96 (1H, m) 

(4) 5-[1-(lsopropyloxycarbonyl)-4-piperidylthio]imidazo[1,2-a]pyridine (Compound 148) 

NMR (200MHz, CDCI3) 5: 1.23 (6H, d, J=6.2Hz), 1.50-1.98 (4H, m), 2.94 (2H, m), 3.37 <1H, m), 4.03 (2H, 
m), 4.91 (1H, heptet, J = 6.2Hz), 7.03 (1H, dd, J = 7, 1.2Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.65 (1H, d, J = 9Hz), 
7.71 (1 H, d, J = 1 .2Hz), 7.97 (1 H, s) 

Example 24 

(1) Synthesis of 5-[2-(tert-butoxycarbonylamino)ethoxy]imidazo[1 ,2-a]pyridine (Compound 149) 



48 

BNSDOCID <EP__CM71236A1 J > 



EP 0 471 236 A1 



To a suspension of 60% sodium hydride (oily; 4.8 g, 0.12 mmoles) in DMF (150 ml) was added a 
solution of 5-chloroimidazo[1 ,2-a]pyridine (15.26 g, 0.1 moles) and 2-aminoethanol (6.72 g, 0.11 mole) in 
DMF (120 ml) with stirring at room temperature and the mixture was stirred at the same temperature for 33 
hours. To the reaction mixture was added di-tert-butyl dicarbonate (32.74 g, 0.15 moles), followed by stirring 

5 at room temperature for 13 hours. After the solvent was distilled off, water (800 ml) was added to the 
residue, which was extracted twice with ether. The extract was washed with water, dried over anhydrous 
magnesium sulfate and concentrated, and then ether was added. The crystals precipitated were filtered off 
and washed with ether to obtain 10.77 g of the desired product (38.8%. colorless crystals). As second 
crystals, 1 .31 g or the desired product was obtained (4.7%, colorless crystals). 

70 NMR (200MHz, CDCI 3 ) 5:1.46 (9H, s), 3.68 (2H, s), 4.31 (2H, t, J = 5.2Hz), 5.00 (1H, br), 6.06 (1H, d, 
J = 7Hz), 7.1 7 (1 H, dd, J = 9, 7Hz), 7.30 (1 H, d, J = 9Hz), 7.60 (1 H, d, J = 1 -2Hz), 7.66 (1 H, s) 

According to the same manner as that described in Example 24 (1), the following compound was 
obtained. 

75 (2) 5-[3-(tert-Butoxycarbonyl)propoxy]imidazo[1 ,2-a]pyridine (compound 150) 

NMR (200MHz, CDCI 3 ) 5:1.44 (9H, s), 2.14 (2H, q, J = 6.2Hz), 3.40 (2H. m), 4.31 (2H, t, J = 6.2Hz), 4.83 (1H, 
br), 6.04 (1H, d, J = 7.2Hz), 7.16 (1H, dd, J = 9, 7.2Hz), 7.28 (1H, d, J = 9Hz), 7.59 (1H, d, J = 1 2Hz), 7.66 
(1H, s) 

20 

Example 25 

(1) Synthesis of 5-[2-(tert-butoxycarbonylamino)ethylsulfonyl]imidazo[1 ,2-a]pyridine (Compound 151) and 5- 
[2-(tert-butoxycarbonylamino)ethylsulfinyl]imidazo[1 ,2-a]pyridine (Compound 152) 

25 

To a solution of 5-[2-(tert-butoxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (2.93 g, 10 mmoles) in 
chloroform (50 ml) was added 85% m-chioroperbenzoic acid (5.08 g, 25 mmoles) under ice-cooling with 
stirring and the mixture was stirred at room temperature for 4 hours. Then, chloroform (50 ml) was added to 
the mixture, which was washed in turn with an aqueous sodium bicarbonate solution and saturated saline, 
30 dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by 
column chromatography (eluent: ethyl acetate) to obtain 560 mg of 5-[2-(tert-butoxycarbonylamino)- 
ethylsulfonyl]imidazo[1 ,2-a]pyridine (Compound 151; 17.2%, colorless crystals) as Fraction 1. 



35 


Elemental analysis for C M Hi 9 N 3 O2S*0.3H 2 O, 




Calcd.: 


C, 50.83; 


H, 5.97; 


N, 12.70 




Found : 


C, 50.97; 


H, 5.91; 


N, 12.80 



NMR (200MHz. CDCI 3 ) 5:1.37 (9H, s), 3.42-3.63 (4H, m), 5.03 (1H, br), 7.36 (1H, dd, J=9.7Hz), 7.68 (1H, 
dd, J = 7, 1.5Hz), 7.85 (1H, d, J = 1.5Hz), 7.96 (1 H, d, J = 9Hz), 8.25 (1H, m) 

As Fraction 2, 5-[2-(tert-butoxycarbonylamino)ethylsulfinyl]imidazo[1 ,2-a]pyridine (Compound 152; 
27.5%, colorless crystals) was obtained. 



45 


Elemental analysis for CnHigNaO* 


S'0.4H 2 O, 




Calcd.: 


C, 53.11; 


H, 6.30; 


N, 13.27 




Found : 


C, 53.27; 


H, 6.18; 


N, 13.36 



Synthesis of S-fphthahmidomethy'thioJimidazop ,2-a]pyridine (Compound 153) 



EP 0 471 236 A1 



to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was 
distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 4.29 
g of the desired product (69.4%, pale yellow crystals). 

NMR (200MHz, CDCI 3 ) 5: 5.10 (2H, s). 7.02-7.13 (2H, m), 7.61-7.84 (6H, m), 7.99 (1H, m) 

5 

Example 27 

Synthesis of 5-[2-(phthalimido)ethylthio]imidazo[1 ,2-a]pyridine (Compound 99) 

w To a suspension of 5-mercaptoimidazo[1 ,2-aJpyridine (3.00g, 20 mmoles) and N-[2-(bromo)ethyl]- 
phthalimide (5.59 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the 
mixture was stirred at room temperature for 3 hours and heated at reflux for 4 hours. After the solvent was 
distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous 
magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatog- 

75 raphy (eluent: ethyl acetate) to obtain 3.95 g of the desired product (61.1%, yellow crystals). 

NMR (200MHz, CDCI 3 ) 5: 3.33 (2H, t, J = 6.6Hz), 3.97 (2H, t, J=6.6Hz), 7.11-7.21 (2H, m), 7.55 (1H, m), 
7.67-7.87 <6H, m) 

Example 28 

20 

Synthesis of 5-[3-(phthalimido)propylthio]imidazo[1 ,2-a]pyridine (Compound 154) 

To a suspension of 5-mercaptoimidazo[1 ,2-a]pyridine (3.00g, 20 mmoles) and N-[3-(bromo)propyl]- 
phthalimide (5.90 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the 

25 mixture was stirred at room temperature for 1 hour and heated at reflux for 1 hour. After the solvent was 
distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous 
magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatog- 
raphy (eluent: ethyl acetate) to obtain 4.79 g of the desired product (71.1%, colorless crystals). 
NMR (200MHz, CDCI3) 5: 2.02 (2H, m), 3.02 (2H, t, J = 7.2Hz), 3.85 (2H, t, J = 6.8Hz), 6.98 (1H, dd, J = 7, 

30 1Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.58 (1H, m), 7.67-7.88 (6H, m) 

Example 29 

Synthesis of 5-[4-(phthalimido)butylthio]imidazo[1 ,2-a]pyridine (Compound 155) 

35 

To a suspension of 5-mercaptoimidazo[1 ,2-a]pyridine (3.00g, 20 mmoles) and N-[4-(bromo)butyl]- 
phthalimide (6.21 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the 
mixture was stirred at room temperature for 1 hour and heated at reflux for 45 minutes. After the solvent 
was distilled off, chloroform was added to the residue, which was washed with saturated saline, dried over 
40 anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column 
chromatography (eluent: ethyl acetate) to obtain 4.50 g of the desired product (64.1%, pale yellow crystals). 
NMR (200MHz, CDCI 3 ) S: 1.62-1.95 (4H, m). 3.04 (2H, t, J = 7Hz), 3.71 (2H, t, J = 6.8Hz), 6.89 (1H, dd, J = 7, 
1Hz), 7.10 (1H, dd, J = 9, 7Hz), 7.54 (1H, d, J = 9Hz), 7.65-7.86 (6H, m) 

45 Example 30 



Synthesis of 5-[6-(phthaiimido)hexylthio]imidazo[1 ,2-a]pyridine (Compound 156) 

To a suspension of 5-mercaptoimidazo[1 ,2-a]pyridine (1.50g, 10 mmoles) and N-[6-(bromo)hexyl]- 
50 phthalimide (3.10 g, 10 mmoles) in ethanol (100 ml) was added triethylamine (2.1 ml, 15 mmoles) and the 
mixture was stirred at room temperature for 12 hours. After the solvent was distilled off, chloroform was 
added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the 
solvent was distilled off. Then the residue was purified by column chromatography (eluent: ethyl acetate) to 
obtain 2.86 g of the desired product (75.5%, light tan solid). 
55 NMR (200MHz, CDCI 3 ) 5: 1.24-1.77 (8H, m), 2.99 (2H, t, J = 7.2Hz), 3.68 (2H, t, J = 7.2Hz), 6.87 (1H, dd, 
J = 7, 1Hz), 7.15 (1H, dd, J = 9, 7Hz), 7.56 (1H, d, J = 9Hz), 7.65-7.88 (6H, m) 

Example 31 

50 



3MSDQOD cEP 0471 236A1 ..I > 



EP 0 471 236 A1 



Synthesis of 5-[2-[2-(phthalimido)ethy!oxy]ethylthio]imidazo[1 ,2-a]pyridine (Compound 157) 

To a suspension of 5-mercaptoimidazo[1 ,2-a]pyridine (3.00g. 20 mmoles) and N-[2-[2-(bromo)ethyloxy]- 
ethyl]phthalimide (5.96 g, 20 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and 

5 the mixture was stirred at room temperature for 12 hours and heated at reflux for 3 hours. After the solvent 
was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous 
magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatog- 
raphy (eluent: ethyl acetate) to obtain 4.00 g of the desired product (54.5%, light tan solid). 
NMR (200MHz, CDCI 3 ) 5: 3.12 (2H, t, J = 6.4Hz), 3.64-3.77 (4H, m), 3.89 (2H, t, J = 5.4Hz), 6.91 (1H, dd, 

70 J = 7.1 Hz). 7.20 (1H, dd, J = 9, 7Hz), 7.56 (1H, d, J = 9Hz), 7.63-7.88 (6H, m) 

Example 32 

According to the same manner as that described in Example 31, the following compounds were 
75 obtained. 

(1) s-[3-[[2-(Anilino)ethyl]-N-(acetyl)amino]propylthio]imidazo[1,2-a]pyridine (Compound 158) 

NMR (200MHz, CDCh) 5: 1.89 (2H, m), 2.05 and 2.09 (each 1.5H, s), 2.97 (2H, m), 3.25-3.60 (6H, m), 6.53- 
20 6.63 (2H, m), 6.63-6.80 (1H, m), 6.89 (1H, m), 7.07-7.25 (3H, m), 7.59 (1H, m), 7.70 (1H, m), 7.83 (1H, s) 

(2) 5-[3-[[2-[N-(acetyl)anilino]ethyl]-N-(acety!)amino]propylthio]imidazo[1 ,2-a]pyridine (Compound 1 59) 

NMR (200MHz, CDCl 3 ) 6: 1.70-2.07 (8H, m), 2.88-3.06 (2H, m), 3.32-3.58 (4H, m), 3.70-3.85 (2H, m), 6.88- 
25 7.00 (1H, m), 7.08-7.26 (3H, m), 7.32-7.50 (3H, m), 7.57-7.68 (1H, m), 7.68-7.74 (1H, m), 7.80-7.88 (1H, m) 

(3) 5-[3-[[2-(anilino)ethyl]-N-(tert-butoxycarbonyl)amjno]propylthio]imidazo[1 ,2-a]pyridine (Compound 1 60) 

NMR (200MHz, CDCI3) 5: 1.45 (9H, s), 1.87 (2H, m), 2.96 (2H, t, J = 7.2Hz), 3.27 (2H, m), 3.34 (2H, m), 6.52- 
30 6.62 (2H, m), 6.69 (1H, dd, J = 9, 7.4Hz), 6.85 (1H, d, J = 7.4Hz), 7.07-7.22 (3H, m), 7.56 (1H, m), 7.69 (1H, 
d, J = 1.4Hz), 7.81 (1H, s) 

(4) 5-[3-[[2-[N-(acetyl)anilino]ethyl]-N-(tert-butoxycarbonyl)amino]propylthio]imidazo[1 ,2-a]pyridine 
(Compound 161) 

35 

NMR (200MHz, CDCI3) &: 1.13-1.48 (9H, m), 1.72-1.98 (5H, m). 2.97 (2H, t, J = 7.2Hz), 3.38 (4H, m), 3.75 
(2H, m), 6.94 (1H. d. J = 7Hz), 7.08-7.47 (6H, m), 7.61 (1H, d, J = 9Hz), 7.70 (1H. d, J = 1 .2Hz), 7.85 (1H, m) 

Example 33 

40 

Synthesis of 5-[2-[2-(hydroxy)benzoylamino]ethylthio]imidazo[1 ,2-a]pyridine (Compound 162) 

To a solution of 5-[2-(amino)ethylthio]imidazo[1 ,2-a]pyridine (3.87 g, 20 mmoles) and triethylamine (5.58 
ml, 40 mmoles) in methylene chloride (200 ml) was added o-acetylsalicyloyl chloride (4.77 g, 24 mmoles) 
45 under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. After the 
solvent was distilled off, ethanol (60 ml) and 1N NaOH (40 ml) were added to the residue, followed by 
strirring for 1 hour. 1N HCI (40 ml) was added and ethanol was distilled off, and then the residue was 
h yv>v- > m r^'.-x.rT- H f -ipH ow^r- ^nhvdrn'iP pn^rjnppii ?m <=!i!fate After the solvent was distilled off 



Elemental analysis for Ci6Hi5N 3 02S, 

! r 32: I K 4 82 I N ■ .1 1 



EP 0 471 236 A1 



(1H, dd, J = 8.6, 7.0Hz), 7.39 (1 H, m), 7.54 (1H, m), 7.68 (1H, d, J = 1.2Hz), 7.77 (1H, m), 7.95 (1H d 
J = 1.2Hz), 9.04 (1 H, br) 

Example 34 

Synthesis of 5-[2-[2H-1 ,3-benzoxazine-2-thion-4(3H)-on-3-yl]ethylthio]imidazo[1 ,2-a]pyridine (Compound 
163) 

To a suspension of 5-[2-[2-(hydroxy)benzoylamino]ethylthio]imidazo[1 ,2-a]pyridine (627 mg, 2.00 
mmoies) in dry tetrahydrofuran (30 ml) was added 1,V-thiocarbonyldiimidazole (713 mg, 4.00 mmoles) and 
the mixture was stirred at room temperature for 46 hours. After the solvent was distilled off, chloroform was 
added to the residue, which was washed with water and dried over anhydrous magnesium sulfate. After the 
solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 
600 mg of the desired product. The product was recrystallized from methylene chloride-ethyl acetate to 
obtain 448 mg of the desired product (63.0%, light red powder). 

NMR (200MHz, CDCI 3 ) 5: 3.45 (2H, m), 4.73 (2H, m), 7.15-7.47 (4H, m), 7.60 (1H, m), 7.71 (1H, d 
J -1.4Hz), 7.75 (1H, m), 7.85 (1H, m), 8.04 (1H, m) 

Example 35 

20 

Synthesis of 5-[2-[2H-1 ) 3-benzooxazine-2,4(3H)-dion-3-yl]ethylthio]imidazo[1 ,2-a]pyridine (Compound 164) 

To a solution of 5-[2-[2-(hydroxy)benzoylamino]ethylthio]imidazo[1 ,2-a]pyridine (627 mg, 2.00 mmoles) 
in dry tetrahydrofuran (30 ml) was added 1 ,1 '-carbonyldiimidazole (649 mg, 4.00 mmoles) and the mixture 
was stirred at room temperature for 15 hours. After the solvent was distilled off, chloroform was added to 
the residue, which was washed with water and dried over anhydrous magnesium sulfate. After the solvent 
was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 528 
mg of the desired product (77.8%, colorless crystals). 

NMR (200MHz, CDCI3) 5: 3.38 (2H, m), 4.34 (2H, m), 7.13-7.33 (3H, m), 7.39 (1H, m), 7.57 (1H, m), 7.67- 
7.78 (2H, m), 7.83 (1H, s), 8.05 (1H, dd, J =7.8, 1.8Hz) 

Example 36 

Synthesis of 5-[1-(trifluoromethanesulfonyl)-4-piperidylthio]imidazo[1 ,2-a]pyridine (Compound 165) 

To a solution of 5-(4-piperidylthio)imidazo[1 ,2-a]pyridine dihydrochtoride (919 mg, 3 mmoles) and 
triethylamine (1.39 ml, 9.89 mmoles) in methylene chloride (40 ml) was added trifluoromethanesulfonic 
anhydride (0.61 ml, 3.63 mmoles) under ice-cooling with stirring and the mixture was stirred at room 
temperature for 1 hour. The residue was washed with saturated saline and dried over anhydrous magnesium 
sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl 
acetate/n-hexane = 1:1) to obtain 0.66 g of the desired product (60.2%, colorless solid). 
Melting point: 102-103* C 

NMR (200MHz, CDCI 3 ) 5: 1.68-1.90 (2H, m), 1.97-2.13 (2H, m), 3.22 (2H, m), 3.41 (1H, m), 3.89 (2H, m), 
7.05 (1H, dd, J = 7, 1.2Hz), 7.17 (1H, dd, J = 8.8, 7Hz), 7.68 (1H, m), 7.72 (1H, d, J = 1 .2Hz), 7.95 (1H, m) 

Example 37 

Synthesis of 5-[4-(methanesulfonamido)butylthio]imidazo[1 ,2-a]pyridine (Compound 166) 

To a solution of 5-[4-(amino)butylthio]imidazo[1 ,2-a]pyridine (440 mg, 1.99 mmoles) and triethylamine 
(0.42 ml, 3.01 mmoles) in methylene chloride (20 ml) was added methanesulfonyl chloride (0.19 ml, 2.45 
mmoles) under ice-cooling with stirring and the mixture was stirred under ice-cooling for 1 hour. The 
reaction mixture was washed in turn with an aqueous saturated sodium bicarbonate solution and saturated 
saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was 
55 purified by column chromatography (eluent: ethyl acetate) to obtain 302 mg of the desired product (50.8%, 
light red brown solid). 

NMR (200MHz, CDCI 3 ) 5: 1.74 (4H, m), 2.94 (3H, s), 3.02 (2H, m), 3.15 (2H, m), 4.53 (1H, br), 6.92 (1H, dd, 
J = 7.1 Hz), 7.1 6 (1 H, dd, J = 9, 7Hz), 7.59 (1 H, m), 7.70 (1 H, d, J = 1 2Hz), 7.84 (1 H, m) 



52 

BMSDCCID: <EP_ .0471236A1J > 



EP 0 471 236 A1 



Example 38 

Synthesis of 5-[4-(trifluoromethanesulfonamido)butylthio]imida2o[1 ,2-a]pyridine (Compound 167) 

5 To a solution of 5-[4-(amino)butylthio]imidazo[1 ,2-a]pyridine (460 mg, 2.08 mmoles) and triethylamine 

(0.44 ml, 3.16 mmoles) in methylene chloride (20 ml) was added trifluoromethanesulfonic anhydride (0.38 
ml, 2.26 mmoles) under ice-cooling with stirring and the mixture was stirred under ice-cooling for 30 
minutes. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. After 
the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to 

70 obtain 277 mg of the desired product (37.7%, colorless crystals). 

NMR (200MHz, CDCI 3 ) 5: 1.74 (4H, m), 3.04 (2H, m), 3.22 (2H, m), 6.94 (TH, dd, J = 7, 1Hz), 7.19 (1H, dd, 
J = 9, 7Hz), 7.56 (1 H, d, J = 9Hz). 7.69 (1 H, d, J = 1 .2Hz), 7.86 (1 H, m), 8.71 (1 H. br) 

Example 39 

75 

Synthesis of 5-[4-(1-naphthalenesulfonylamino)butvlthiolimidazo[1 ,2-a]pyridine (Compound 168) 

To a solution of 5-[4-(amino)butylthio]imidazo[1 ,2-a]pyridine (300 mg, 1.36 mmoles) and triethylamine 
(0.29 ml, 2.08 mmoles) in methylene chloride (15 ml) was added 1-naphthalenesulfonyl chloride (307 mg, 

20 1.35 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 1 hour. 
The reaction mixture was washed in turn with an aqueous sodium bicarbonate solution and water and dried 
over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column 
chromatography (eluent: ethyl acetate) to obtain 296 mg of the desired product (53.0%, colorless solid). 
NMR (200MHz, CDCh) 6: 1.55 (4H, m), 2.81 (2H, m), 2.92 (2H, m), 4.83 (1H, br), 6.78 (1H, dd, J = 7, 1Hz), 

25 7.11 (1H, dd, J = 9, 7Hz), 7.45-7.75 (6H, m), 7.93 (1H, m), 8.05 (1 H, d, J = 8.4Hz), 8.25 (1 H, dd, J = 7.2, 
1.2Hz), 8.62 (1H, m) 

Example 40 



30 Synthesis of 5-[4-(isopropyloxycarbonylamino)butylthio]imidazo[1 ,2-a]pyridine (Compound 169) 

To a solution of 5-[4-(amino)butylthio]imidazo[1 ,2-ajpyridine (370 mg, 1.67 mmoles) and triethylamine 
(0.35 ml, 2.51 mmoles) in metylene chloride (20 ml) was added isopropyl chloroformate (0.25 g, 2.04 
mmoles) under ice-cooling with stirring and the mixture was stirred under ice-cooling for 1 hour. The 
35 reaction mixture was washed in turn with an aqueous sodium bicarbonate solution and saturated saline and 
dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by 
column chromatography (eluent: ethyl acetate) to obtain 215 mg of the desired product (41.8%, light tan oily 
product). 

NMR (200MHz, CDCI3) 6: 1.22 (6H, d. J=6.2Hz), 1.54-1.72 (4H, m), 3.02 (2H, m), 3.18 (2H, m). 4.66 (1H, 
40 br), 4.90 (1H, hept, J = 6.2Hz), 6.90 (1 H, dd, J=7, 1Hz), 7.15 (1H. dd, J=9, 7Hz), 7.58 (1H, d, J=9Hz), 7.84 
(1H, m) 

Example 41 

45 Synthesis of 5-[3-(benzenesulfonamido)propyloxy]imidazo[1 ,2-a]pyridine (Compound 170) 

To a suspension of 5-[3-(amino)propyloxy]imidazo[1 ,2-a]pyridine dihydrochloride (2.64 g, 10 mmoles) 



«.;fr. thb crude product tnus ontamea was r^crystai Tun motr yicne-cthanu. tu ob:air i 9/ g of thb 
desired product (59.5%, light brown crystals). 
Melting point: 155-156* C 



r . - 4.'- 



EP 0 471 236 A1 



Synthesis of 5-[2-[2-(methanesuitonamido)ethyloxy]ethylthio]imidazo[1 ,2-a]pyridine (Compound 171) 

To a suspension of 5-[2-[2-(phthalimido)ethyloxy]ethylthio]imida2o[1 ,2-a]pyridine (1.10 g, 3 mmoles) in 
ethanol (15 ml) was added hydrazine monohydrate (0.44 ml, 9.1 mmoles) and the mixture was heated at 

5 reflux for 1 hour. After the mixture was cooled by standing, methylene chloride (30 ml) was added and an 
insoluble product was filtered off, and then the solvent was distilled off from the filtrate. Methylene chloride 
(30 ml) and triethylamine (0.84 ml, 6 mmoles) were added to the residue, to which was further added 
methanesulfonic anhydride (679 mg, 3.9 mmoles) under ice-cooling with stirring and the mixture was stirred 
at room temperature for 1 hour. Then, it was washed with saturated saline and dried over anhydrous 

70 magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography 
(eluent: ethyl acetate/ethanol = 10:1) to obtain 0.82 g of the desired product (86.9%, pale yellow oily 
product). 

NMR (200MHz, CDCI 3 ) 5: 2.96 (3H, s), 3.16 (2H, t, J = 6Hz), 3.22 (2H, m), 3.54 (2H, t, J = 5Hz), 3.68 (2H, t, 
J = 6Hz), 5.12 (1H, br), 6.99 (1H, dd, J = 7, 6Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.61 (1H, m), 7.70 (1H, d. 
75 J = 1.2Hz), 7.88 (1H, m) 

Example 43 

Synthesis of 5-[3-[1 ,2-benzisothiazole-3(2H)-on-1 ,1 -dioxido-2-yl]porpylthio]imidazo[1 ,2-a]pyridine 

20 (Compound 172) 

To a solution of 5-[3-(chloro)propylthio]imidazo[1 ,2-a]pyridine (1.17 g, 5.16 mmoles) and saccharin (1.50 
g, 8.19 mmoles) in DMF (30 ml) was added 1 ,8-diazabicyclo[5.4.0]-7-undecene (0.78 ml, 5.22 mmoles) and 
the mixture was stirred at 80* C for 24 hours. The reaction mixture was poured into an aqueous sodium 
25 bicarbonate solution, which was extracted with ethyl acetate. The extract was washed with water and dried 
over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column 
chromatography (eluent: ethyl acetate) to obtain 658 mg of the desired product (34.1%, colorless crystals). 
Melting point: 99-100* C 

NMR (200MHz, CDCI 3 ) B: 2.17 (2H, m), 3.09 (2H, t, J = 7Hz), 3.95 (2H, t, J = 6.8Hz), 7.00 (1H, dd, J = 7, 
30 1Hz), 7.16 (1H, dd, J = 8.8, 7Hz), 7.60 (1H, m), 7.69 (1H, d, J = 1.2Hz), 7.80-7.97 (4H, m), 8.06 (1H, m) 

Example 44 

Synthesis of 5-[3-(methanesulfonamido)benzyl]imidazo[1 ,2-a]pyridine (Compound 173) 

35 

To a solution of 3-aminobenzy! alcohol (1.23 g, 10 mmoles) and triethylamine (3.07 ml, 22 moles) in 
methylene chloride (50 ml) was added methanesulfonyl (1.55 ml, 20 mmoles) under ice-cooling with stirring 
and the mixture was stirred at room temperature for 1 hour. Then, 5-mercaptotmidazo[1 ,2-a]pyridine (1.50 g, 
10 mmoles) and triethylamine (1.40 ml, 10 mmoles) were added, followed by stirring for 5hours. The 
40 mixture was washed in turn with an aqueous saturated solid bicarbonate solution and saturated saline and 
dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by 
column chromatography (eluent: ethyl acetate) to obtain 0.88 g of the desired product (26.4%, light brown 
product). 

NMR (200MHz, CDCI 3 ) 5: 2.91 (3H, s), 4.13 (2H, s), 6.52 (1H, m), 6.81 (1H, m), 6.92-7.28 (4H, m), 7.58 (1H, 
45 m), 7.66 (1H, m), 7.86 (1H, m) 

Example 45 

Synthesis of 5-[3-(acetyloxy)propylthio]imidazo[1 ,2-a]pyridine (Compound 174) 

50 

To a solution of 5-[3-(hydroxy)propylthio]imidazo[1 ,2-a]pyridine (2.00 g, 9.60 mmoles) and triethylamine 
(1.60 ml, 11.5 mmoles) in methylene chloride (50 ml) was added acetic anhydride (1.10 ml, 11.6 mmoles) 
with stirring at room temperature and the mixture was further stirred at room temperature for 7.5 hours. The 
reaction mixture was washed with an aqueous 1N sodium hydroxide solution and dried. After the solvent 
55 was distilled off, the residue was purified by column chromatography [eluent: hexane/acetone (1:1)] to 
obtain 2.40 g of the desired product (100%, brown oily product). 

NMR (200MHz, CDCI 3 ) 5 : 1 .98 (2H, quint, J = 6.6Hz), 2.04 (3H, s), 3.06 (2H, t, J = 7.0Hz), 4.19 (2H, t, 
J=6.2Hz), 6.94 (1H, d, J = 6.8Hz), 7.17 (1H, dd, J = 8.8, 6.8Hz), 7.62 (1H, d, J = 8.8Hz), 7.71 (1H, s), 7.85 

54 

BMSDOCID: <E° 0471236A1 \_ , 



EP 0 471 236 A1 



(1H, s) 

IR (Neat) cm" 1 : 1740, 1488, 1240 
Example 46 

5 

Synthesis of 5-[3-(acetyloxy)propylthio]imidazo[1 ,2-a]pyridine (Compound 174) 

To a solution of 3-bromo-1-propanol (0.50 g, 3.60 mmoles) and triethylamine (0.60 ml, 0.40 mmoles) in 
methylene chloride (15 ml) was added acetic anhydride (0.40 ml, 4.24 mmoles) with stirring at room 

70 temperature and the mixture was further stirred at room temperature overnight. The reaction mixture was 
washed with an aqueous 1N sodim hydroxide solution and dried. After the solvent was distilled oft, ethanol 
(10 ml) and triethylamine (1.00 ml, 7.17 mmoles) was added to the residue. To the mixture was added 5- 
mercaptopyridine (0.49 g, 3.26 mmoles) with stirring at room temperature and the mixture was stirred at 
room temperature for 5 minutes. The solvent was distilled off and the residue was purified by column 

75 chromatography [eluent: hexane/acetone (1:1)] to obtain 0.54 g of the desired product (66.3%, brown oily 
product). 

NMR (200MHz, CDCI 3 ) 5 : 1 .98 (2H, quint, J = 6.6Hz), 2.04 (3H, s), 3.06 (2H, t, J = 7.0Hz), 4.19 (2H, t, 
J = 6.2Hz), 6.94 (1H, d, J = 6.8Hz), 7.17 (1H, dd, J = 8.8, 6.8Hz), 7.62 (1 H, d, J = 8.8Hz), 7.71 (1H, s), 7.85 
(1H, s) 

20 IR (Neat) cm" 1 : 1740, 1488, 1240 
Example 47 

Synthesis of 5-[3-(benzoyloxy)propylthio]imidazo[1 ,2-a]pyridine (Compound 175) 

25 

To a solution of 5-[3-(hydroxy)propylthio]imidazo[1 ,2-a]pyridine (1.00 g, 4.80 mmoles) and triethylamine 
(0.80 ml, 5.74 mmoles) in methylene chloride (25 ml) was added benzoyl chloride (1.10 ml, 11.6 mmoles) 
with stirring at room temperature and the mixture was further stirred at room temperature for 30 minutes. 
The reaction mixture was washed with an aqueous 1N sodium hydroxide solution and dried. After the 
30 solvent was distilled off, the residue was purified by column chromatography [eluent: hexane/acetone (1:1)] 
to obtain 1.32 g of the desired product (88.1%, white solid). 
Melting point: 60-61 " C 



35 


Elemental analysis for C17H16N2O2S, 


Calcd.: 


C, 65.36; 


H, 5.16; 


N, 8.97 




Found : 


C, 65.52; 


H, 5.17; 


N, 8.84 



NMR (200MHz, CDCi 3 ) 5 : 2.13 {2H, quint, J = 6.6Hz), 3.16 (2H, t, J = 7.2Hz), 4.46 (2H, t, J = 6.2Hz). 6.96 
(1H, d, J = 7.0Hz), 7.15 (1H, dd, J = 9.2. 7.0Hz), 7.38-7.64 <4H, m), 7.69 (1H, s), 7.86 (1H, s), 7.99 (2H, dd, 
J = 7.2, 1.6Hz) 

IR (Neat) cm" 1 : 1713, 1487, 1280 
Example 48 

Synthesis of 5-[3-[2-(phenyl)ethylcarbonyloxy]propylthio]imidazo[1 ,2-a]pyridine (Compound 176) 



solvent was distilled off, the residue was purified by column chromatography [eluent: hexane acetone (1.1)] 
to obtain 1.37 g of the desired product (84.2%, yellow oily product). 



EP 0 471 236 A1 



Elemental analysis for Cishbo^C^S, 


Calcd.: 
Found : 


C. 67.03; 
C, 66.86; 


H, 5.92; 
H, 6.01; 


N, 8.23 
N, 7.81 



NMR (200MHz, CDCI 3 ) 5 : 1 .92 (2H, quint. J=6.6Hz), 2.63 (2H, t, J = 7.7Hz), 2.94 (4H, t, J = 7.2Hz), 4.19 
(2H. t, J = 6.2Hz), 6.91 (1 H, d, J = 7.2Hz), 7.10-7.35 (6H, m), 7.61 (1H, d, J = 9.0Hz), 7.72 (1H, s), 7.84 (1H, 
s) 

IR (Neat) cm" 1 : 1730, 1487, 1288 
Example 49 

Synthesis of 5-[3-(acetyloxy)propylsulfinyl]imidazo[l ,2-a]pyridine (Compound 177) and 5-[3-(acetyloxy)- 
propylsulfonyl]imidazo[1,2-a]pyridine (Compound 178) 

To a solution of 5-[3-(acetyloxy)propylthio]imidazo[1 ,2-a]pyridine (1.00 g, 3.99 mmoles) in chloroform 
(25 ml) was added m-chloroperbenzoic acid (1.47 g, 5.96 mmoles) with stirring under ice-cooling and the 
mixture was further stirred under ice-cooling for 1.5 hours. The reaction mixture was washed in turn with an 
aqueous 20% sodium bisulfite solution and an aqueous saturated sodium bicarbonate solution and dried. 
After the solvent was distilled off, the residue was purified by column chromatography [eluent: 
hexane/acetone (1:1)] to obtain 0.19 g of 5-[3-(acetyloxy)propylsu!finyi]imidazo[1 ,2-a]pyridine (Compound 
177) (34.6%, yellow oily product) and 0.19 g of 5-[3-(acetyloxy)propylsulfonyl]imidazo[1 ,2-a]pyridine 
(Compound 178) (16.5%, yellow oily product). 

5-[3-(acetyloxy)propylsulfinyl]imidazo[1 ,2-a]py ridine (Compound 1 77) 

NMR (200MHz, CDCI 3 ) 6 : 1.90-2.30 (2H, m), 2.02 (3H, s), 3.05-3.30 (2H, m), 4.10-4.30 (2H, m), 7.31-7 38 
<2H, m), 7.47-7.87 (2H, m), 7.92 (1H, s) 
IR (Neat) cm" 1 : 1740, 1240, 1063, 1033 

5-[3-(acetyloxy)propylsulfonyl]imidazo[1 ,2-a]pyridine (Compound 1 78) 

NMR (200MHz, CDCI 3 ) 5 : 1.98 (3H, s), 2.03-2.20 (2H, m), 3.30-3.40 (2H, m), 4.13 (2H, t, J = 6.2Hz), 7.36 
(1 H, dd, J = 9.0, 7.2Hz), 7.68 (1 H, dd J = 7.2, 1 .2Hz), 7.86 (1 H, s), 7.96 (1 H, d, J = 9.0Hz), 8.28 (1 H, s) 
IR (Neat) cm -1 : 1740, 1325, 1240, 1130 

Example 50 

Synthesis of 5-[3-(methoxy)propylthio]imidazo[1 ,2-a]pyridine(Compound 179) 

To a solution of 5-[3-(hydroxy)propylthio]imidazo[1 ,2-a]pyridine (803 mg, 3.86 mmoles) in 
tetrahydrofuran (30 ml) was added 60% sodium hydride in oil (0.19 g, 4.6 mmoles) with stirring under ice- 
cooling and the mixture was further stirred under ice-cooling for 30 minutes. To the reaction mixture was 
added methyl iodide (0.36 ml, 5.8 mmoles), followed by stirring at room temperature overnight. The reaction 
mixture was poured into water, which was extracted with methylene chloride (30 ml x 3). The methylene 
chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled 
off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 308 mg of the 
desired product (35.9%, light brown oily product). 

NMR (200MHz, CDCI 3 ) 5 : 1.92 (2H, tt, J = 6.0, 7.2Hz), 3.10 (2H, t, J=7.3Hz), 3.32 (3H, s), 3.48 (2H, t, 
J = 5.8Hz), 6.91 (1H, dd, J = 1.2, 7.0Hz), 7.15 (1H, dd, J = 7.2, 9.0Hz), 7.57 (1 H, td, J = 1.0, 9.0Hz), 7.70 (IK 
d, J = 1 .2Hz), 7.84 (1 H, t, J = 0.8Hz) 

Example 51 

Synthesis of 5-[3-(phenoxy)propylthio]imidazo[1 ,2-a]pyridine (Compound 180) 
(1) Synthesis of 5-[3-(methanesulfonyloxy)propylthio]imidazo[1 ,2-a]pyridine 



56 

BNSDOCID' <EP^ 0471236A1 J > 



EP 0 471 236 A1 



To a solution of 5-[3-(hydroxy)propytthio]imidazo[1 ,2-a]pyridine (1.030 g, 4.95 mmoles) and 
triethylamine (1.03 ml, 7.4 mmoles) in methylene chloride (30 ml) was added methanesulfonyi chloride (0.46 
ml, 5.9 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 
minutes. The reaction mixture was washed with water and the aqueous layer was extracted with methylene 
5 chloride (30 ml x 3). The methylene chloride layers were combined and dried over anhydrous magnesium 
sulfate. Then, the solvent was distilled off to obtain crude 5-[3-(methanesulfonyloxy)propylthio]imidazo[1 ,2- 
a]pyridine as a yellow oily product. 

(2) Synthesis of 5-[3-(phenoxy)propylthio]imidazo[1 ,2-a]pyridine (Compound 180) 

10 

To a solution of phenol (0.70 g, 7.4 mmoles) in tetrahydrofuran (20 ml) was added 60% sodium hydride 
in oil (0.30 ml, 7.4 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice- 
cooling for 30 minutes. To the reaction mixture was added a solution of crude 5-[3-(methanesulfonyloxy)- 
propylthio]imidazo[1 ,2-a]pyridine obtained in the above (1) in tetrahydrofuran (10 ml), followed by heating 
75 under reflux overnight. The reaction mixture was poured into water, which was extracted with methylene 
chloride (30 ml x 4) The methylene chloride layers were combined and dried nver anhydrous megnesium 
sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl 
acetate) to obtain 1.220 g of the desired product (86.8%, light brown oily product). 

NMR (200MHz, CDCI 3 ) 6 : 2.13 (2H, tt, J = 5.9, 7.1Hz), 3.22 (2H, t ( J = 7.2Hz), 4.09 (2H, t, J = 5.8Hz), 6.85- 
20 7.00 (4H, m), 7.13 (1H, dd, J = 7.0, 9.0Hz), 7.25-7.33 (2H, m), 7.57 (1H, td, J =0.8, 9.0Hz), 7.71 (1H, d, 
J = 1.4Hz), 7.85 (1H, s) 

Example 52 

25 Synthesis of 5-[3-[2-(phenoxy)ethyloxy]propylthio]imidazo[1 ,2-a]pyridine (Compound 181) 

(1) Synthesis of 1-methanesulfonyloxy-2-(phenoxy)ethane 

To a solution of 2-(phenoxy)ethanol (1.35 g, 9.78 mmoles) and triethylamine (2.04 ml, 14.7 mmoles) in 
30 methylene chloride (30 ml) was added methanesulfonyi chloride (0.91 ml, 12 mmoles) with stirring under 
ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction solution was 
washed with water and the aqueous layer was extracted with methylene chloride (30 ml x 3). The methylene 
chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled 
off, the residue was subjected to column chromatography [eluent: hexane/methyl (1:1)] to obtain crude 1- 
35 methanesulfonyloxy-2-(phenoxy)ethaneas a pale yellow oily product. 

(2) Synthesis of 5-[3-[2-(phenoxy)ethyloxy]propylthio]imidazo[1 ,2-a]pyridine (Compound 181) 

To a solution of 5-[3-(hydroxy)propylthio]imidazo[1 .2-a]pyridine (1.018 g, 4.89 mmoles) in 
40 tetrahydrofuran (20 ml) was added 60% sodium hydride in oil (0.30 ml, 7.4 mmoles) with stirring under ice- 
cooling and the mixture was further stirred under ice-cooling for 30 minutes. To the reaction mixture was 
added a solution of crude 1-methanesulfonyloxy-2-(phenoxy)ethane obtained in the above (1) in 
tetrahydrofuran (10 ml), followed by heating under reflux for 4.5 hours. The reaction solution was poured 
into water, which was extracted with methylene chloride (30 ml x 4). The methylene chloride layers were 
45 combined and dried over anhydrous megnesium sulfate. After the solvent was distilled off, the residue was 
purified by column chromatography (eluent: ethyl acetate) to obtain 0.870 g of the desired product (54.2%, 
light brown oily product). 



tixamp e bo 

Synthesis of 5-[3-[3-(phenyi)propyloxy]propylthio]imidazo[1 ,2-a]pyridine (Compound 182) 



EP 0 471 236 A1 



methyl iodide(1 .53 g, 7.71 mmoles), followed by stirring at room temperature overnight. The reaction 
mixture was poured into water, which was extracted with methylene chloride (30 ml x 3). The methylene 
chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled 
off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 0.987 g of the 
5 desired compound (58.9%, light brown oily product). 

NMR (200MHz, CDCI 3 ) 5 : 1.81-1.99 (4H, m), 2.68 (2H, t, J = 7.6Hz), 3.12 (2H, t, J = 7.2Hz), 3.41 (2H, t, 
J = 6.4Hz), 3.51 (2H, t, J = 5.8Hz), 6.91 (1H, dd, J = 1.1, 7.1Hz), 7.10-7.32 (6H, m), 7.56 (1H, td, J = 1.0, 
9.0Hz), 7.69 (1 H, d, J = 1 .4Hz), 7.84 (1 H, t, J = 1 .0Hz) 

70 Example 54 



Synthesis of 5-[3-[2-(anilino)ethyloxy]propylthio]imidazo[1 ,2-a]pyridine 
(Compound 183) 

75 (1) Synthesis of 5-[3-(methanesulfonyIoxy)propylthio]imidazo[1 ,2-a]pyridine 

To a solution of 5-[3-(hydroxy)propylthio]imidazo[1 ,2-a]pyridine (2.003 g, 9.62 mmoles) and 
triethylamine (2.01 ml, 14.4 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride 
(0.89 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 
20 10 minutes. The reaction mixture was washed with water and the aqueous layer was extracted with 
methylene chloride (30 ml x 3). The methylene chloride layers were combined and dried over anhydrous 
magnesium sulfate. Then, the solvent was distilled off to obtain crude 5-[3-(methanesulfonyloxy)propylthio]- 
imidazo[1 ,2-a]pyridine as a yellow oily product. 

25 (2) Synthesis of 5-[3-[2-(anilino)ethyloxy]propylthio]imidazo[1 ,2-a]pyridine (Compound 183) 

To a solution of 2-anilinoethanol (1.98 g, 14.4 mmoles) in tetrahydrofuran (20 ml) was added 60% 
sodium hydride in oil (1.15 ml, 28.9 mmoles) with stirring under ice-cooling and the mixture was further 
stirred under ice-cooling for 30 minutes. To the reaction mixture was added a solution of crude 5-[3- 

30 (methanesulfonyloxy)propylthio]imidazo[1 ,2-a]pyridine obtained in the above (1) in tetrahydrofuran (10 ml), 
followed by heating under reflux for 1 hour. The reaction mixture was poured into water which was extracted 
with methylene chloride (30 ml x 4). The methylene chloride layers were combined and dried over 
anhydrous megnesium sulfate. After the solvent was distilled off, the residue was purified by column 
chromatography (eluent: ethyl acetate) to obtain 0.951 g of the desired product (30.2%, light green 

35 crystals). 

NMR (200MHz, CDCI 3 ) 5 : 1 .94 (2H, tt, J = 5.9, 7.1Hz). 3.10 (2H, t, J=7.2Hz), 3.28 (2H, t, J = 5.2Hz), 3.57 
(2H, t, J = 6.0Hz), 3.62 (2H, t, J = 5.1 Hz), 3.98 (1 H, br, s), 6.63 (2H, d, J = 7.3Hz), 6.72 (1H, t, J = 7.3Hz), 6.89 
(1H, dd, J = 1.0, 7.4Hz), 7.10-7.22 (3H, m), 7.57 (1H, d, J = 9.0Hz), 7.70 (1H, d, J = 1.4Hz), 7.83 (1H, s) 

40 Example 55 

Synthesis of 5-[3-[2-(N-methanesulfonylanilino)ethyloxy]propylthio]imidazo[1 ,2-a]pyridine (Compound 184) 

To a solution of 5-[3-[2-(phenylamino)ethyloxy]propylthio]imidazo[1 ,2-a]pyridine (1.034 g, 3.158 
45 mmoles) and triethylamine (0.88 ml, 6.3 mmoles) in methylene chloride (30 ml) was added methanesulfonyl 
chloride (0.37 ml, 4.7 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice- 
cooling for 10 minutes. The reaction mixture was washed with water and the aqueous layer was extracted 
with methylene chloride (30 ml x 3). The methylene chloride layers were combined and dried over 
anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column 
50 chromatography (eluent: ethyl acetate) to obtain 16 mg of the desired product (brown oily product) 

NMR (200MHz, CDCIa) h : 1 .86 (2H, tt, J = 5.9, 7.2H), 2.92 (3H, s), 3.03 (2H, t, J = 7.2Hz), 3.50 (2H, t, 
J = 5.3Hz), 3.50 (2H, t, J = 5.8Hz), 3.84 (2H, t, J=5.7Hz), 6.89 (1 H, dd, J = 1.0, 7.0Hz), 7.15 (1H, dd, J = 7.0, 
9.0Hz), 7.31 -7.40 <5H, m), 7.57 (1 H, d, J = 9.0Hz), 7.70 (1 H, d, J = 1 .0Hz), 7.82 (1 H, s) 

55 Example 56 



Synthesis of 5-[1 -(2-thienylcarbonyl)-4-piperidyloxy]imidazo[1 ,2-a]pyridine (Compound 185) 



58 

BNSDOCIO <EP_ __04?i 2 36Al _t_> 



EP 0 471 236 A1 



To a suspension of 60% sodium hydride in oil (0.40 g, 10 mmoles) in dimethylformamide (30 ml) was 
added 1 -(2-thienylcarbonyl)-4-hydroxypiperidine (2.11 g, 10 mmoles) with stirring under ice-cooling and the 
mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added 5- 
chioroimidazo[1 ,2-a]pyridine (1.53 g, 10 mmoles) with stirring under ice-cooling, followed by stirring at room 
5 temperature for 7 hours. Water was added to the reaction mixture, which was extratced with ethyl acetate 
and dried. After the solvent was distilled off, the residue was purified with column chromatography [eluent: 
ethyl acetate/hexane (1:1) — ethyl acetate/hexane (2:1) — ethyl acetate/ethanol (50:1)] to obtain 0.15 g of 
the desired product (4.6%, pale yellow oily product). 

NMR (200MHz, CDCI 3 ) 5 : 2.03-2.16 (4H, m), 3.85-3.96 (4H, m), 4.84-4.93 (1H, m), 6.09 (1 H, d, J = 7.0Hz), 
70 7.06 (1H, dd, J = 3.6, 5.0Hz), 7.12-7.35 (3H, m), 7.47 (1H, dd J = 1.2, 5.0Hz), 7.62 (1H, d, J = 1.2Hz), 7.67 
(1H, d, J = 0.8Hz) 

Example 57 

75 Synthesis of 5-[2-(N-benzylmethylsulfonylamino)ethyloxy]imidazo[1 ,2-a]pyridine (Compound 186) 

(1) Synthesis of 2-(N-benzylmethylsulfonylamino)1-ethanol 

To a solution of N-benzylamino ethanol (7.10 ml, 50 mmoles) and triethylamine (7.67 ml, 55 mmoles) in 
20 dichloromethane (100 ml) was added methylsulfonyl chloride (4.26 ml, 55 mmoles) with stirring under ice- 
cooling and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed 
in turn with an aqueous saturated sodium bicarbonate solution and water and dried. After the solvent was 
distilled off, the residue was purified by column chromatography [eluent: ethyl acetate/hexane (1:1) — > ethyl 
acetate/hexane (2:1) — • ethyl acetate] to obtain 1.99 g of the desired product (17.4%, pale yellow oily 
25 product). 

NMR (200MHz, CDCI 3 ) 5 : 1.89 (1H, bs), 2.94 (3H, s), 3.37 (2H, t, J = 5.0Hz), 3.65 (2H, t, J = 5.0Hz), 4.47 
(2H, s), 7.35-7.39 (5H, m) 

IR (Neat) cm" 1 : 3520, 3030, 2930, 1600, 1595, 1455, 1320, 1140 

30 (2) Synthesis of 5-[2-(N-benzylmethylsulfonylamino)ethyloxy]imidazo[1 ,2-a]pyridine (Compound 186) 

To a suspension of 60% sodium hydride in oil (0.20 g, 5 mmoles) in dimethylformamide (20 ml) was 
added 2-(N-benzylmethylsulfonylamino)-1 -ethanol (1.14 g, 5 mmoles) with stirring under ice-cooling and the 
mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added 5- 
35 chloroimidazo[1,2-a]pyridine (0.763 g, 5 mmoles) with stirring under ice-cooling, followed by stirring at 80* C 
for 16 hours. After cooling, water was added to the reaction mixture, which was extratced with ethyl acetate 
and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: 
ethyl acetate/hexane (1:1) — ethyl acetate/hexane (2:1)] to obtain 0.68 g of the desired product (39.4%, pale 
yellow oily product). 

40 NMR (200MHz, CDCI3) 5 : 2.94 (3H, s), 3.72 (2H, t, J = 6.0Hz), 4.23 (2H, t, J = 5.8Hz), 4.52 (2H, s) t 5.87 (1H, 
d, J = 6.8Hz), 7.11 (1H, d, J =7.2, 9.0Hz), 7.25-7.40 (6H, m), 7.58 (2H, s) 
IR (Neat) cm" 1 : 3150, 3030, 2930, 1640, 1540 

Example 58 

45 

Synthesis of 5-[3-(methylsulfonylamino)propylthio]imidazo[1 ,2-a]pyridine (Compound 27) 

/M c; V nthp^ic n* q-nn.P + hv lc "' ilfnn v'aminn-1 -methvlsu'fonvlovvpronane 



■. junny arc Ifit.; mutur u wai; s'^nuu <.«: ! ooti !u' npuf atjf l. Ju mirutuL ' rucn..i:u'. iri.xi.Lro a c jo wasr 
in turn with an aqueous sodium bicarbonate and water and dried. Afte r the solvent was distihed off. the 
residue was purified by column chromatography (eluent: ethyl acetate) to obtain 24.22 g of the desired 



■?x\ ; - 5 V 4 



EP 0 471 236 A1 



(2) Synthesis of 5-[3-{methy!sulfonylamino)propylthio]innidazo[1 ,2-a]pyridine (Compound 27) 

To a solution of 5-mercaptoimidazo[1 ,2-a]pyridine (1.50 g, 10 mmoles) and 4M sodium methylate (2.93 
ml, 12 mmoles) in ethanol (50 ml) was added 3-methylsulfonylamino-1-methylsulfonyloxypropane (2.77 g, 
5 12 mmoles) at room temperature and the mixture was heated under reflux for 16 hours. After cooling, the 
solvent was distilled off. The residue was dissolved in chloroform, washed with an aqueous saturated 
sodium bicarbonate solution and dried. After the solvent was distilled off, the residue was purified by 
column chromatography [eluent: ethyl acetate/ethanol (50:1)] to obtain 1.34 g of the desired product (47.5%, 
pale yellow crystals). 
10 Melting point: 114-116* C 

NMR (200MHz, CDCI3) 5 : 1.92 (2H, quint, J=6.8Hz), 2.95 (3H, s), 3.09 (2H, t, J = 7.0Hz), 3.30 (2H, q, 
J = 6.6Hz), 4.82 (1H, bs), 6.94 (1H, d, J = 7.0Hz), 7.15 (1H, dd, J = 7.0. 9.0Hz), 7.60 (1H, d, J = 9 0Hz) 7 69 
(1H, s), 7.84 (1H, s) 

IR (KBr) cm' 1 : 3440, 3080, 2850, 1615, 1485, 1315, 1140 

75 

Example 59 

Synthesis of 5-[1 -(methylsulfonyl)-4-piperidylsulfinyl]imidazo[1 ,2-a]pyridine (Compound 1 87) and 5-[1 - 
(methylsulfonyl)-4-piperidylsulfonyl)imidazo[1,2«a]pyridine (Compound 188) 

To a solution of 5-[1-(methy!sulfonyl)-4-piperidylthio]imidazo[1 ,2-a]pyridine (0.934 ml, 3.0 mmoles) in 
chloroform (30 ml) was added m-chloroperbenzoic acid (0.914 g, 4.5 mmoles) with stirring under ice-cooling 
and the mixture was stirred at room temperature for 2 hours. To this reaction mixture was added m- 
chloroperbenzoic acid (0.609 g, 3.0 mmoles) with stirring under ice-cooling and the mixture was stirred at 
room temperature for 1 hour. The reaction mixture was washed with an aqueous 1N sodium hydroxide 
solution and dried. After the solvent was distilled off, the residue was purified by column chromatography 
[eluent: ethyl acetate/ethanol (25:1 — 10:1)] to obtain 0.272 g of the sulfone compound (24.2%, white 
crystals) as Fraction 1 and 0.273 g of the sulfoxide compound (26.5%, white crystals) as Fraction 2. 

ao 5-[1-(methylsulfonyl)-4-piperidylsulfonyl]imidazo[1,2-a]pyridine (Compound 188) 

Melting point: 224-226 *C 

NMR (200MHz, CDCI3) 5 : 1.96-2.12 (4H, m), 2.68-2.82 (1H, m), 2.79 (3H, s), 3.22 (1H, m), 3.85-3.97 (2H, 
m), 7.36 (1 H, dd, J = 7.2, 8.8H2), 7.64 (1 H, d, J = 7.2Hz), 7.86 (1 H, bs), 7.98 (1 H, d, J = 9.0Hz), 8.34 (1 H, bs) 

5-[1 -(methyisuIfonyl)-4-piperidylsulfinyl]imidazo[1 ,2-a]pyridine (Compound 1 89) 

Melting point: 205* C (decomp.) 

NMR (200MHz, CDCIa) 6 : 1.69-2.08 (4H, m), 2.66-2.85 (1 H, m), 2.79 (3H, s), 3.29 (1H, m), 3.82-3.79 (2H, 
40 m), 7.25-7.38 (2H, m), 7.81-7.86 (2H, m), 8.09 (1H, bs) 

Example 60 

Synthesis of 5-[2-[3-(hydroxy)isoindolin-1-one-2-yl]ethylthio]imidazo[1 ,2-aJpyridine (Compound 189) 

To a suspension of 5-mercaptoimidazo[1 ,2-a]pyridine (159 mg, 1 mmole) and 2-[2-(bromo)ethyl]-3- 
hydroxyindolin-1-one (256 mg, 1 mmole) in ethanol (15 ml) was added trimethylamine (0.21 ml, 1.5 
mmoles) and the mixture was stirred at room temeperature for 12 hours and heated under reflux for 2 
hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water 
and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by 
column chromatography [eluent: ethyl acetate/ethanol (10:1)] to obtain 11.9 g of the desired product (36.6%, 
pale yellow solid). 

NMR (200MHz, CDCI 3 -DMSO-d 6 ) 5 : 3.38 (2H, m), 3.88 (2H, m), 5.82 (1H, m), 6.47 (1H, m), 7.14-7.67 (2H, 
m), 7.44-7.67 (5H, m), 7.76 (1H, m), 7.85 (1H, m) 

Example 61 

Synthesis of 5-[2-{isoindolin-1 -one-2-yl)ethylthio]imidazo[1 ,2-a]pyridine (Compound 190) 

60 

BNSDOClO: <EP C471236A1 J > 



EP 0 471 236 A1 



To a suspension of 5-mercaptoimidazo[1 ,2-a]pyridine (150 mg, 1 mmole) and 2-[2-(bromo)ethyl]- 
isoindolin-1 -one (240 mg, 1 mmole) in ethanol (15 ml) was added triethylamine (0.21 ml, 1.5 mmoles) and 
the mixture was stirred at room temperature for 12 hours and heated at reflux for 2 hours. After the solvent 
was distilled off, chloroform was added to the residue which was washed with water and dried over 
5 anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column 
chromatography [eluent: ethyl acetate/ethanol (15:1)] to obtain 238 mg of the desired product (77.0%, light 
brown solid). 

NMR (200MHz, CDCI 3 ) & : 3.32 (2H, t, J=6.8Hz), 3.89 (2H, t, J = 6.8Hz), 4.39 (2H, s), 7.05-7.18 (2H, m), 
7.37-7.60 (4H, m), 7.70 (1H, d, J = 1 2Hz), 7.82-7.88 (2H, m) 

70 

Example 62 



Synthesis of 5-[2-(phenylsulfonylamino)ethylsulfiny!]imidazo[1 ,2-a]pyridine (Compound 191) 

75 To a suspension of 5-[2-(phenylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine (600 mg, 1.8 mmoles) in 

chloroform (50 ml) was added m-chloroperbenzoic acid (913 mg, 4.5 mmoles) with stirring under ice-cooling 
and the mixture was stirred at room temperature for 22 hours. The reaction mixture was washed in turn with 
an aqueous 1N sodium hydroxide solution and saturated saline and dried over anhydrous magnesium 
sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl 

20 acetate/ethanol(10:1)] to obtain 200 mg of the desired product (31.8%, light brown solid). 

NMR (200MHz, CDCl 3 ) 5 : 3.16 (1 H, m), 3.35-3.65 (3H, m), 5.96 (1H, br), 7.28-7.36 (2H, m), 7.48-7.67 (3H, 
m), 7.75-7.90 (5H, m) 

Example 63 

25 

Synthesis of 5-[2-(tert-bothoxycarbonylamino)ethylthio]-3-nitroimidazo[1 ,2-a]pyridine (Compound 192) 

To a solution of cysteamine (2.95 g, 38.2 mmoles) in DMF (50 ml) was added 60% sodium hydride in 
oil (1.53 g, 38.2 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 

30 10 minutes. To the mixture was added 5-chloro-3-nitroimidazo[1 ,2-a]pyridine (5.81 g, 29.4 mmoles), 
followed by stirring under ice-cooling for 30 minutes and further stirring at room temperature for 30 
minuters. Di-tert-butyl dicarbonate (9.62 g, 44 mmmles) was added, followed by stirring at room tempera- 
ture for 4 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate, 
washed with water and dried over anhydrous magensium sulfate. After the solvent was distilled off, the 

35 residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.06 g of the desired 
product (20.7%, tan solid). 

NMR (200MHz, CDCI 3 ) 6 : 1 .41 (9H, s), 3.17-3.41 (4H, m), 5.00 (1H, br), 7.36 (1H, dd, J = 6.2, 2.6Hz), 7.59- 
7.71 (2H, m). 8.54 (1H, s) 

40 Example 64 



Synthesis of 5-[2-(methylsulfonylamino)ethytthio]-3-nitroimidazo[1 ,2-a]pyridine (Compound 193) 
(1) Synthesis of 5-[2-(amino)ethylthio]-3-nitroimidazo[1 ,2-a]pyridine*dihydrochloride 

45 

To a suspension of 5-[2-(tert-butoxycarbonylamino)ethylthio]-3-nitroimidazo[1 ,2-a]pyridine (364 mg, 1.08 
mmoles) in methanol (3 ml) was added cone, hydrochloric acid (2 ml) and the mixture was stirred at room 

tompnraturp for 1 hour Thon +hp solvent was disti"od off to obtain 340 rnrj of thp rjostrnr) oror1ro+ 



To a solution of 5-[2-(amino)ethylthio]-3-nitroimidazo[ 1 .2-a]pyridine "dihydrochlcride (221 mg. 0.71 
mmole) and triethylamine (0.33 ml. 2.37 mmoles) in methylene chloride (30 ml) was added methanesulfonyl 

- I- H.-. (O rp ' 1 OO r-o ,>-,-! r. <r . : * «- c A rr-'.rr : ; ^ O o * : -rr.r l : n -j ^ ^, H f^r. m. : V * ■; r n ,v~,S * , ,r*Y m P- f c;*irrH * l ~ " 



EP 0 471 236 A1 



NMR (200MHz, CDCI 3 ) 6 : 2.84 (3H, s), 3.09 (3H, s), 3.33 (2H, m). 7.24 (1H, br), 7.65 (1H, m), 7.77-7.90 (2H, 
m), 8.78 (1H, s) 

Example 65 

5 

Synthesis of 5-[1 -(methylsulfonyl)-4-piperidyloxy]-3-nitroimida2o[1 ,2-a]pyridine (Compound 194) 

To a solution of 4-hydroxy-1 -methylsulfonyipiperidine (2.15 g, 12 mmoles) in dimethylformamide (3 ml) 
was added 60% sodium hydride in oil (0.48 g, 12 mmoles) with stirring under ice-cooling and the mixture 

w was stirred at room temperature for 10 minutes. To the reaction mixture was added 5-ch!oro-3-nitroimidazo- 
[1,2-a]pyridine (1.976 g, 10 mmoles) with stirring under ice-cooling and the mixture was stirred at the same 
temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl 
acetate. The precipitate was filtered off, washed with water and dried to obtain 1.862 g of the desired 
product (54.7%, yellow solid). The organic layer was washed with water and dried over anhydrous 

75 magnesium sulfate. After the solventy was distilled off, the crude crystalls thus obtained were recrystallized 
from methylene-n-hexane to obtain 460 mg of the desired product (460 mg, tan solid). 

NMR (200MHz, CDCI3) 5 : 2.02-2.23 (3H, s), 2.90 (3H, s), 3.29 (2H, m), 3.66 (2H, m), 4.95 (1 H, m), 6.44 (1H, 
d, J = 7.6Hz), 7.43 (1 H, d, J = 8.8Hz), 7.58 (1 H, dd, J = 8.8, 7.6Hz), 8.40 (1 H, s) 

20 Example 66 

Synthesis of 3-amino-5-[1 -(methylsulfonyl)-4-piperidyloxy]imidazo[1 ,2-a]pyridine (Compound 195) 

To a solution of 5-[1-(methylsulfonyl)-4-piperidyloxy]-3-nitroimidazo[1 ,2-a]pyridine (70 mg, 0.226 mmole) 
25 in methylene chloride (10 ml) was added 10% palladium-carbon (50 ml) and the mixture was stirred in 
hydrogen atmosphere at room temperature for 1.5 hours. After the reaction mixture was treated with Cellite, 
the solvent was distilled off. To the residue was added chloroform, which was washed in turn with an 
aqueous saturated sodium bicarbonate solution and water and dried over anhydrous magnesium sulfate. 
After the solvent was distilled off, the residue was purified by column chromatography [eluent: 
30 chloroform/methanol (15:1)] to obtain 93 mg of the desired product (30.0%, brown oily product). 

NMR (200MHz, CDCI3) 5 : 2.17 (4H, m), 2.84 (3H, s), 3.28-3.53 (4H, m), 4.70 (1H, m), 5.87 (1H, dd, 
J = 7.2Hz), 6.87 (1 H, dd, J = 9, 7.2Hz), 7.07 (1 H, d, J = 9Hz), 7.27 (1 H, s) 

Example 67 

35 ~ 

Synthesis of 2-isobutylcarbamoyl-5-[2-(methylsulfonylamino)ethylthio][1 ,2-a]pyridine (Compound 196) 

A mixture of 2-ethoxycarbonyl-5-[2-(methylsulfonylamino)ethylthio][1 ,2-a]pyridine (148 mg, 0.431 
mmole), isobutylamine (0.86 ml, 8.65 mmoles) and ethanol (10 ml) was heated under reflux for 18 hours. To 

40 the mixture was further added isobutylamine (1.72 ml, 17.3 mmoles) and the mixture was heated under 
reflux for 17 hours. To the mixture was further added isobutylamine (1.72 ml., 17.3 mmoles) and the mixture 
was heated under reflux for 8 hours. After the solvent was distilled off, the residue was purified by column 
chromatography (eluent: ethyl acetate) to obtain 139 mg of the desired product (86.9%, pale yellow solid). 
NMR (200MHz, CDCI3) 5 : 1 .00 (6H, d, J = 6.6Hz), 1.93 <1H, nonet, J = 6.6Hz), 2.98 (3H, s), 3.15-3.43 (6H, 

45 m), 5.51 (1H, brt, J = 6Hz), 7.10 (1H, dd, J = 7, 1.2Hz), 7.24 (1H, dd, J = 9, 7Hz), 7.49 (1H, br), 7.55 (1H, m), 
8.47 (1H, s) 

Example 68 

50 According to the same manner as that described in Example 31, the following compound was obtained. 

5-[3-[N-(methylsulfonyl)-3-(phenyl)propylamino]propylthio]imidazo[1,2-a]pyridine (Compound 197) 

NMR (200MHz, CDCI3) 5 : 1.80-2.00 (4H.), 2.62 (2H, t, J = 7.6Hz), 2.80 (3H, s), 3.02 (2H, t, J = 7Hz), 3.17 
55 (2H, m), 3.28 (2H, m), 6.91 (1H, dd, J = 7, 1Hz), 7.07-7.34 (6H, m). 7.59 (1H, d, J = 9Hz), 7.85 (1H,m) 

Example 69 



62 

BNSDOC1D: <EP. 0471236A1.J_> 



EP 0 471 236 A1 



Synthesis of 5-[1 -(methylsulfonyl)-4-piperidylthio]imidazo[1 ,2-a]pyridine (free compound of Compound 29) 

(1) Synthesis of 1 -methylsulfonyl-4-methylsulfonyloxypiperidine 

5 To a solution of 4-hydroxypiperidine (5.10 g, 50 mmoles) and triethylamine (20.9 ml, 150 mmoles) in 

methylene chloride (150 ml) was added methanesulfonyl chloride (8.54 ml, 110 mmoles) with stirring under 
ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed in 
turn with an aqueous saturated sodium bicarbonate solution and saturated saline and dried over anhydrous 
magnesium sulfate. After the solvent was distilled oft, the residue was solidified with ethyl acetate-n-hexane 

ro to obtain 11.45 g of the desired product (88.3%, pale yellow solid). 

NMR (200MHz, CDCI 3 ) 5 : 2.07 (4H, s), 2.81 (3H, s), 3.36 (4H, m). 4.93 (1H, m) 

(2) Synthesis of 5-[1 -(methylsulfonyl)-4-piperidylthio]imidazo[1 ,2-a]pyridine (free compound of Compound 
29) 

75 

To a suspension of 5-mercaptoimidazo[1 ,2-a]pyridine (1.50 g, 10 mmoles) in ethanol (100 ml) was 
added a solution of 4.1 M sodium methylate (2.44 ml, 10 mmoles) in methanol and the mixture was stirred 
at room temperature for 10 minutes. To the reaction mixture was added 1-methylsulfonyl-4-methylsul- 
fonyloxypiperidine (2.83 g, 11 mmoles) at room temperature and the mixture was heated under reflux for 14 

20 hours. After the solvent was distilled off, the residue was dissolved in chloroform, which was washed in turn 
with an aqueous 1N sodium hydroxide solution and water and dried over anhydrous magnesium sulfate. 
After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl 
acetate/ethanol (10:1)] to obtain 1.27 g of the desired product (40.8%, light brown solid). 
NMR (200MHz, CDCh) 5 : 1.70-2.13 (4H, m), 2.79 (3H, s), 2.90 (2H, m), 3.35 (1 H, m), 3.69 (2H, m), 7.05 

25 (1H, dd, J = 7, 1.2Hz), 7.17 (1H, dd, J = 8.8, 7Hz), 7.67 (1H. d, J = 8.8Hz), 7.71 (1H, d, J = 1.2Hz), 7.96 (1H, 
s) 

Preparation 1 



(1) Compound 1 


100 g 


(2) Lactose 


50 g 


(3) Corn starch 


15 g 


(4) Carboxymethylcellulose calcium 


44 g 


(5) Magnesium stearate 


1 9 


1,000 Tablets 


210 g 



All the components (1), (2) and (3) and 30 g of the component (4) were kneaded with water, dried under 
40 vacuum and granulated. The granulated powder was mixed with 14 g of the component (4) and 1 g of the 
component (5) and the mixture was charged in a tabletting machine to obtain 1,000 tablets containing 100 
mg of the component (1) per one tablet. 

Preparation 2 



(1) Compound 1 | 10 g 



All the components were thoroughly admixed and filied into a suitable gel'atin caosule tc obtain 100 



EP 0 471 236 A1 



( 1 ) Compound 2 10 g 

(2) Sodium chloride 1.8 g 

(3) Distilled water for injection suitable amount 
Total amount 200 ml 



w 

The component (3) was added to all the components (1) and (2) to dissolve them and the total amount 
of the solution was adjusted to 200 ml. Then, the solution was sterilized and filled into ampoules of suitable 
size to obtain 100 ampoules containing 100 mg of the component (1) per one ampoule. 

T5 Experiment 1 

Calmodulin inhibitory activity 

(Experimental method) 

20 

To a reaction system (0.45 ml) composed of 50 mM Tris-HCI buffer (pH 7.4), 5 mM MgCb, 10 uM 
CaCI 2 and carmodulin [2 units; manufactured by Sigma Co., p-0270] or 3mM EGTA, cyclic nucleotide 
phosphodiesterase [0.01 unit; manufactured by Sigma Co., p-0520], and 1 uM cGMP ([ 3 H]cGMP, containing 
3nCi) was added the compound of the present invention obtained in the above Example (1% DMSO 
25 solution, 50 ul) and the reaction was carried out at 37* C for 15 minutes. Then, the reaction was terminated 
by boiling the tubes for 2 minutes. The [ 3 H]5*-GMP products was converted to [ 3 H]guanosine by additional 
incubation at 37 "C for 10 minutes with 50 ug of snake venom (C. atrox), as 5'-nucleotidase. Following the 
addition of carrier guanosine, into the reaction tubes Dowex 1 x 8 resin was added, and the tubes were 
centrifuged for 1 minute. Radioactivity in the 250 uJ of supernatant was counted. The determination of the 
30 inhibition was according to the following formula. 

% Inhibition = 100 - (count in the presence of a medicine - count in the presence of EGTA)/(count in 
the absence of a medicine - count in the presence of EGTA) x 100 

The results are shown in Table 1 . 

35 



40 



45 



50 



55 



64 

DOCID <EP C471236A1 



EP 0 471 236 A1 



70 



75 



20 



25 



30 



> 



c 



C 



X 



35 



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> 



u X 

>s O 
O 

c 



o 

C 

o 
a. 
E 
o 



i 

^ o 
o 



o 
c 

3 

o 

CL 

e 
o 
o 



O 



m 

oo 



CM 



On r- 



CN CN 

oo f"- 



o 



O 
00 



O 



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<r o 



o 
o 



co 



o 

vO 



cm sr 



NO 



oo 



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o 



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w 



15 



20 



25 



30 



35 



X 



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> 



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I 

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o 

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c 



o 

C 
O 

o. 
E 

o 



> 



o 



o 
c 

3 
O 
CL 

e 

o 
u 



o 



o 



O 



O 
vX3 



o 



vO CO 



ltn 



CO 



00 



m 



vO 

rn 



oo 



vO 



oo 

SO 



OA 



vD u-n. 



CM 



to 



r*- o «n 

v£) ITS 



m 
oo 



CO 



ON 
CO 



O 



O 



O 



On 00 
O ^ 



40 



As shown in Table 1, the compounds of the present invention have excellent calmodulin inhibitory 
activity. 



Experiment 2 



45 



Hypotensive activity in spontaneous hypertensive rat (SHR) 
(Experimental method) 



50 



SHR male rats of twenty weeks old were used. They were warmed in an incubator at 37* C for 5 
minutes and the measurement was conducted according to Plethysmograph method. Medicines (the 
compounds in the above Examples) were suspended in gum arabic-water and were orally administered in 
an amount of 2.5 ml/kg. Blood pressure was measured before administration of medicines, at 1 hour and at 
5 hours after administration, and the change of the value from that before administration was determined, 
respectively. 

The results are shown in Table 2. 



55 



66 

BNSDOCID: <EP _ _0471236A1 J_> 



EP 0 471 236 A1 



Table 2 

Hypotensive activity 

5 



Compound No. Dose Change of blood pressure 

(mg/kg) 1 hour 5 hours 



1 


100 


-11 . 2 


-11.5 


28 


100 


-13-5 


-43.0 


64 


i nn 

.A. w w 


_ "» i n 


_ m A 
A / • U 


67 


100 


-15.0 


-22.0 


69 


100 


-7.0 


-32.0 



As shown in Table 2, the compounds of the present invention have excellent hypotensive activity. 

25 

Experiment 3 

Effect on incidence of arrhythmia caused by ischemia and following reperfusion in rat heart 
30 (Experimental method) 

Male Sprague Dawley rats (Japan Clea) of 9 to 10 weeks old were anesthetized with 50 mg/kg (i.p.) of 
sodium pentobarbital. The heart was exposed by a left thoractomy under artificial ventilation with room air 
and silk suture was placed under the main left coronary artery (LAD) to ligate for 5 minutes. Then, the 

35 ligature was released again for reperfusion. The incidence of ventricular tachycardia (VT), ventricular 
fibrillation (VF) and cardiac arrest (CA) caused until 10 minutes after reperfusion were noted. Medicines 
(compounds obtained in the above Examples) were orally administered (5 ml/kg) at 1 hour before tightening 
the ligature. The effect of medicines were estimated in comparison with the frequency of a group received a 
vihicle according to XMest. 

40 The results are shown in Table 3 below. 



45 



EP 0 471 236 A1 



Table 3 

Effect on incidence of arrhythmia caused by 

ischemia and following reperfusion in rat heart 



JO 


Compound No. 


Dose 


VT 


VF 


CA 






(mg/kg) 


( Frequency ) 


75 


1 


10 


2/4 


2/4 


1/4 




1 


30 


1/4 


1/4 


0/4 




14 


10 


1/3 


0/3 


0/3 


20 


26 


10 


2/3 


1/3 


1/3 




32 


30 


1/3 


1/3 


1/3 


25 


64 


30 


1/3 


1/3 


1/3 




118 


30 


1/3 


1/3 


0/3 




127 


30 


1/3 


1/3 


0/3 


30 


vehicle 




7/7 


7/7 


2/7 



As shown in Table 3, the compounds o1 the present invention decrease the frequency of arrhythmia 
35 induced by 5 minutes of occlusion followed by reperfusion. 

Experiment 4 

Effect on acute renal failure caused by ischemia and following reperfusion in rat kidneys. 

40 

(Experimental method) 

SD rats (male) of 6 to 7 weeks old were anesthetized with pentobarbital sodium (50 mg/kg, i.p.) and 
bilateral renal arteries were ligated. After 45 minutes, a crip was removed to reperfuse. After 20 hours, blood 
45 was collected from abdominal aorta under anesthesia with pentobarbital sodium and blood urea nitrogen 
(BUN) was measured. Medicines (compounds obtained in the above Examples) were administered (5 
m g/kg) 1 hour before occulusion of renal artery. 

The results are shown in Table 4. 

50 



55 



68 



BNSDOCID: <EP 047123SA1 J ..> 



EP 0 471 236 A1 



Table 4 

Effect on acute renal failure caused by ischemic 
renal/reper fusion in rat 



70 



Compound No, 



Dose 
(mg/kg) 



Blood urea ni t rogen 
(mg/kg) 



75 



10 



83.3 ± 20.4 



20 



30 



71.1 ± 11.4 



25 



50 



65.6 ± 5.1 



30 



vehicle 



118.2 ± 5.0 



As shown in Table 4, the compounds of the present invention depress the increase in BUN in ischemic 
35 renal/reperfusion of rats. 

Another aspect of the present invention to provide novel angiogenesis inhibitors. 

It is well known that angiogenesis occurs in normal physiologic conditions of human or mammal such as 
embryogenesis and ovulation or piacentation caused by female sexual cycle, wound healing, restoration 
process of inflammation, and in various morbidity wherein blood capillaries rapidly form and increase to 

40 cause serious damage to tissue and the like shown as follows. As the diseases caused by such a pathologic 
increase of blood capillaries, for example, there have been known diabetic retinopathy, retrolental 
fibroplasia, angiogenesis accompanying keratoplasty, glaucoma, opthalmic tumor and trachoma and the like 
in the opthalmologic field; psoriasis, suppurative granuloma and the like in the dermatologic field; angioma, 
fibrous angioma and the like in the pediatric field; hypergenic cicatrix, granulation and the like in the surgical 

45 field; arthritis rhuematica, edematous sclerosis and the like in the medical field; atherosclerosis and the like 
in cardiac diseases; various tumors and the like. 

Particularly, a lot of people become blindness by abnormal increase of angiogenesis in diabetic 
rptinonathv ard trqrhnm?. Fnrthor a lot nf ppnnlp Fwffe' fmnn h r oakaqr of ^artilaqo hv ah^orrmal an- 



✓ ascuianzation induced Ly an angioyunsis 'actor wmcn is produced by tumor cells. Inerefcro, i: «s expected 
that a an angiogenesis inhibitor becomes a new medicine for treatment of various tumors and studies on 
angiogenesis inhibitors have been started [J. Folkman. Advance in Cancer Research, 43, 175 (1985), edited 



EP 0 471 236 A1 



Further, it has been recognized that angiogenesis inhibitory activity is synergistically exhibited by using 
sulfated a, /3, and 7-cyclodextrin, particularly, & -cyclodetrin tetradecasuifate or heparin in combination with 
an angiostatic steroid as described above, fumagillin, a collagen synthesis inhibitor or the like [D. Ingber and 
J. Folkman, Laboratory Investigation, 59, 44 (1988)]. 

5 On the other hand, U.S. Patent No7 4,599,331 discloses that angiogenesis inhibitory activity is observed 

by using a steroid (etianic acid derivative) alone. However, this steroid has also strong adrenocorticosteroid 
hormone activity and, therefore, there is a large dufficulty to use it as a medicine. 

There has been a lot of reports concerning imidazo[1 ,2-a]pyridine derivatives. However, there are few 
reports of a pharmacological activity concerning a compound wherein an alkylthio group having a functional 

io group is bound at 5-position thereof. Particularly, regarding such a compound having a carbamate ester as 
the functional group, only 5-(2-tert-butoxycarbonylaminoethylthio)imidazo[1 ,2-a]pyridine and 5-[2-(N- 
chloroacetylcarbamoyloxy)ethylthio]imidazo[1 ,2-a]pyridineare reported as a starting material of synthesis of 
cephem compounds having excellent antibacterial activity in European Patent Application P871 081 89.9. 
However, there is no description about a pharmacological activity thereof. 

75 Under these circumstances, the present inventors have synthesized various imidazo[1 ,2-a]pyridine 

derivatives having a substituent at 5-position and intensively studied their pharmacological activities. As a 
result, it has been found that some of them have excellent angiogenesis inhibitory activities. 
*- Thus, the present invention also provides a novel angiogenesisinhibitory composition comprising a 

compound of the formula (1): 

20 




wherein A' is a divalent C1-15 hydrocarbon group which may contain ethereal oxygen at any possible 
position and a branched part of the hydrocarbon group may be substituted; R a and R b are the same or 
different and are a hydrogen, an optionally substituted hydrocarbon group, a halogen, a nitro group, a 
nitroso group, an optionally protected amino group, a lower alkoxycarbonyl group or a lower alkyl carbamoyl 
35 group; R c is a hydrogen or an optionally substitued hydrocarbon group or may form a ring together with the 
carbon atom of A; and R d is an optionally substituted hydrocarbon group, or a salt thereof. 
In the formula (1), examples of the group represented by A' include the formula: 



40 



45 



R G R9 R 1 
I I I 

~(C) X -(C) -(C) 2 - 

>f 'h '-i 
R f R h 

wherein x, y and z are integers of 0 to 5, respectively; R e ,R f , R 9 , R h , R 1 and R j are a hydrogen, or an 
optionally substituted lower alkyl, lower alkenyl, aralkyl, aryl, or heterocyclic group; or R e and R f or R g and 
R h or R 1 and R j may bind together to form a ring, or R e or R g may bind together with R j or R j to form a ring, 
-CH2CH2OCH2CH2- or the formula: 



50 



55 



-CCH,)a^ <CHl)b - 

wherein a and b are integers of 0 to 5, respectively and the like. 

Examples of the lower alkyl group represented by R e , R\ R 9 , R\ R' and R j include a straight or 
branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 



70 

BNSOOCID: <EP_ _ 0471 236A1 J. > 



EP 0 471 236 A1 

sec-butyl, tert-butyl, pentyt, hexyl and the like. Examples of the lower alkenyl group represented by R e , R\ 
R 9 , R h , R 1 and R' include a lower alkenyl group having 2 to 6 carbon atoms such as vinyl, ally!, 2-butenyl, 3- 
butenyl and the like. The lower alkyl and lower alkenyl group may have 1 to 5 substituents and examples 
thereof include halogen, nitro, amino, lower alkylamino, cyclic amino, lower alkoxy, aryloxy, carbamoyl, 
5 cyano, hydroxy, carboxy, lower alkoxycarbonyl, lower alkylcarbamoyl and the like. Examples of halogen 
include fluoro, bromo, chloro and iodo. 

Examples of the lower alkylamino group as the above substituent include a N-monoalkylamino group of 
which alkyl moiety has 1 to 6 carbon atoms such as methylamino, ethylamino. propylamino, butylamino and 
the like, and a N,N-dialkylamino group of which alkyl moiety has 1 to 6 carbon atoms such as 
70 dtmethylamino, diethylamino, dibutylamino, methylethylamino and the like. 

Examples of the cyclic amino group as the above substituent include a 4 to 7 membered cyclic amino 
group such as N-pyrrolidino, piperazino, piperadinyl, morpholino, homopiperazino and the like. 

Examples of the lower alkoxy group as the above sustituent include a straight or branched alkoxy group 
having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy and the like. 
75 Examples of the aryloxy group as the above substituent include a C6-10 aryloxy group such as phenoxy, 1- 
naphthoxy, 2-naphthoxy and the like. Examples of the lower alkoxycarbonyl group as the above substituent 
include an alkoxycarbonyl group of which alkoxy moiety has 1 to 6 carbon atoms such as methoxycarbonyt, 
ethoxycarbonyl propoxycarbonyl, butoxycarbonyl and the like. Examples of the lower alkylcarbamoyl group 
as the above substituent include a N-monoalkylcarbamoyl group of which alkyl moiety has 1 to 6 carbon 
20 atoms such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl and the like and a N,N- 
dialkylcarbamoyl group of which alkyl moiety has 1 to 6 carbon atoms such as dimethylcarbamoyl, 
diethylcarbamoyl, dibutylcarbamoyl, methylethylcarbamoyl and the like. 

As the aralkyl group represented by R e , R\ R 9 , R h , R' and R j , for example, there is a phenyl lower alkyl 
group of which alkyl moiety has 1 to 6 carbon atoms such as benzyl, phenethyl, 3-phenylpropyl, 4- 
25 phenylbutyl and the like and a naphthyl-lower alkyl of which alkyl moiety has 1 to 6 carbon atoms such as 
(l-naphthyl)methyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl and the like. The phenyl moiety of the phenyl- 
lower alkyl group and the naphthyl part of the naphthyl-lower alkyl group may be substitued with 1 to 4 
substituents such as halogen, lower alkyl, lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, 
carbamoyl, lower alkylcarbamoyl and the like. Examples of halogen include fluoro, bromo, chloro and iodo. 
30 Examples of the lower alkyl group and the lower alkenyl group include those similar to the lower alkyl group 
or a lower alkenyl group represented by R e , R\ R 9 , R h , R l and R 1 . As the lower alkoxy group, for example, 
there is a straight or branched alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, 
isopropoxy, butoxy, pentoxy and the like. As the lower alkoxycarbonyl group, for example, there are an 
alkoxycarbonyl group of which alkoxy moiety has 1 to 6 carbon atoms such as methoxycarbonyl, 
35 ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like. As the lower alkylcarbamoyl group, for 
example, there are a N-alkylcarbamoyl group of which alkyl moiety has 1 to 6 carbon atoms such as 
methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl and the like, and a N,N-dialkylcar- 
bamoyl group of which alkyl moiety has 1 to 6 carbon atoms such as dimethylcarbamoyl, diethylcarbamoyl, 
dibutylcarbamoyl, methylethylcarbamoyl and the like. 
40 As the aryl group represented by R e , R\ R g , R h , R' and R J . for example, there are an aromatic 

monocyclic, bicyclic or tricyclic hydrocarbon group such as phenyl, 1 -naphthyl, 2-naphthyl, phenanthryl, 
anthryl and the like, and examples of the heterocyclic group include an aromatic monocyclic group or 
bicyclic hetero ring bound via carbon atoms, which contains 1 to 4 hetero atoms such as sulfur, oxygen, 
nitrogen and the like, such as thienyl, furyl, benzothienyl, benzofranyl and the like. The aryl group and the 
45 heterocyclic group may be substituted with 1 to 4, preferably 1 or 2 substituents such as halogen, lower 
alkyl, lower alkoxy, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl, lower alkylcar- 
bamoyl and the like. Examples of halogen in the above substituents include fluoro, bromo, chloro and iodo. 
As the lower alkyl aroup for example there is the alkyl qrouo having 1 to 6 carbon atoms as described 



,.i'KL><v 'TK.' : uty f.ai . :».. o _afL_i, atu'".o Ac !t'n l M;f a.Kyu_ar uan oy jr^up. r example. inoru \C a N 
monoalkylcarbamoyl group of which alkyl moiety has 1 to 6 carbon atoms and a N,N-dialkylcarbamoyl 
group of which alky! moiety has 1 to 6 carbor atoms. Examples of these groups include groups similar to 

r.r *' rr , lower a'k^vv nrr,-. : r, *-c ir.'.vr-'- alk^wca'r; or yi grcjp and th-; ; ov,'rr a'kv'narbamcv' orn.c as t^n 



EP 0 471 236 A1 



cycloalkane such as cyclopropane, cyclobutane, cyclohexane and the like. As the ring formed by binding R e 
or R g with R h or R\ for example, there is C3-8 cycloalkane such as cyclopropane, cyclobutane, cyclopen- 
tane, cyclohexane, cycloheptane and the like. 

As the optionally substituted hydrocarbon group in R a and R b p for example, there are a lower alkyl 

5 group, a lower alkenyl group, an aralkyl group and an aryl group which are optionally substituted with the 
substituents in the above group represented by A'. Further, examples of halogen include fluoro, chloro, 
bromo and iodo. As the optionally protected amino group, for example, there are an amino group, an 
acylamino group and the like. As the acyl group of the above acylamino group, there is a group represented 
by -COR d or -C02R d , for example, a lower alkylcarbonyl group (e.g. C1 -&alky!carbonyl group such as 

70 acetyl, etc.), aralkylcarbonyl group (e.g. C7-10 aralkylcarbonyl group such as benzylcarbonyl, etc.), 
arylcarbonyl group (i.e C&-io aryl-carbonyl group such as benzoyl, etc.), a lower alkyloxycarbonyl group 
(e.g. C1-4 alkyloxycarbonyl group such as methoxycarbonyl, etc.), aralkyloxycarbonyl group (e.g. C7-10 
aralkyloxycarbonyl group such as benzyloxycarbonyl, etc.), aryloxycarbonyl group (e.g. Cs-10 ary- 
loxycarbonyl group such as phenoxycarbonyl, etc.) and the like. 

75 As the lower alkoxycarbonyl group and the lower alkylcarbamoyl group in R a and R b , for example, there 
is a group similar to a lower alkoxycarbonyl group and a lower alkylcarbamoyl group as the substituent of 
the phenyl moiety in the arakyl group represented by R e , R f , R 9 , R h , R j and R ] . 

As the optionally substituted hydrocarbon group of R c and R d , for example, there are an optionally 
substituted lower alkyl group, a lower alkenyl group, a cycloalkyl group, an aralkyl group, an aryl group and 

20 the like. As the optionally substituted lower alkyl group, the lower alkenyl group, aralkyl group and aryl 
group, for example, there is a group similar to those described with respect to the group represented by A'. 
As the cycloalkyl group, for example, there is a cycloalkyl group having 3 to 8 carbon atoms such as 
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. As the substituent of 
the cycloalkyl group, for example, there are those similar to the substituent of the optionally substituted 

25 lower alkyl group as described in A' and the number thereof is 1 to 5. Examples of the group wherein R c is 
connected with R e , R f , R 9 , R\ R' or R* in A' to form a ring include a group represented by the formula: 



40 wherein Q and R are 2 or 3, repectiveiy. 

The compound of the formula (1) can form, for example, an acid addition salt with an inorganic acid 
such as hydrochloric acid, hydrobromic acid, sulfuric acid, phophoric acid or the like and an organic acid 
such as acetic acid, oxalic acid, methanesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, 
lactic acid or the like. 

45 The compound (1) or a salt thereof may be a solvate and examples of a solvent of the solvate include 

alcohols such as methanol, ethanol, propanol, isopropanol and the like; ketones such as acetone and the 
like; ethers such as tetrahydrofuran, dioxane and the like. 

As the preferred embodiment of the compound of the above formula (1) or a salt thereof, for example, 
there is a compound represented by the formula: 



30 




35 




50 



55 



72 



BNSDOCiD: <EP. 



0471236A1 I 



EP 0 471 236 A1 



5 




d') 



SCH 2 CH 2 N-C0 2 R d ' 
i 

H 

70 

wherein R a is a hydrogen or a lower alkyl group; R b ' is a hydrogen or an optionally substituted lower alkyl 
group; and R d is an optionally substituted lower alkyl group, a cycloalkyl group or a lower alkenyl group, or 
a salt thereof. 

In the formula (V), examples of the lower alkyl group represented by R a , the optionally substituted 
/5 lower alkyl group represented by R b , and lower alkyl group and lower alkenyl group represented R d include 
those described with respect to the groups represented by R e . R f . R 9 . R\ R' and R j . Examples of the 
optionally substituted lower alkyl group represented by R d include those described in the above R d . R d is 
preferably Ci-& alkyl or Ci -e alkenyl. 

The compound (1) may contain an assymetric carbon in the molecule. When stereoisomers of R-and S- 
20 configurations are present, not only these isomers, but also a mixture thereof are included in the scope of 
the present invention. 

lmidazo[1 ,2-a]pyridine derivatives (1) of the present invention or a salt thereof can be synthesized, for 
example, according to the following method. 
(A) A compound of the formula: 

25 



30 




wherein X' is a halogen such as chloro, bromo, iodo or the like and R a and R b are as defined above is 
reacted with a compound of the formula: 

35 

HS-A' -N-C0 9 R d (3) 



40 wherein A', R c and R d are as defined above, or a salt thereof. 
(B) A compound of the formula: 




X A -A ' -N-C0 0 R 



(5) 



EP 0 471 236 A1 



as methanesulfonyloxy group, or a salt thereof. 
(C) A compound of the formula: 



5 



70 




I 



wherein A', R a , R b and R c are as defined above, or a salt thereof is reacted with a compound of the 
75 formula: 

X'-C0 2 R d (7) 

wherein R d and X 1 are as defined above. 
20 (D) A compound of the formula: 



25 




H 

30 

wherein A', R a , R b and R d are as defined above, or a salt thereof is reacted with a compound of the 
formula: 



X^H C (9) 

35 

wherein X 1 is as defined above and R c is an optionally substituted hydrocarbon group. 
(E) A compound of the formula: 



(10) 



S-A'-NCO 



wherein A', R a and R b are as defined above is reacted with a compound of the formula: 



R d OH (11) 

50 

wherein R d is as defined above. 
(F) A compound of the formula: 



55 




74 



BNSDOCID: <EP 0471 236A1 _l _> 



EP 0 471 236 A1 



5 




S-A'-NCOX 2 



(12) 



R c 



70 

wherein X 2 is a leaving group such as halogen (e.g. chloro, etc.), phenoxy group, imidazolyl and the like 
and A', R a , R b and R c are as defined above, or a salt thereof is reacted with a compound of the formula: 

R d OH (11) 

J5 

wherein R d is as defined above. 
(G) A compound of the formula; 



wherein A', R a , R c and R d are as defined above, or a salt thereof is reacted with a halogenating agent to 



20 




25 



S-A L N-C0 2 R d 



30 



obtain a compound of the formula: 



35 




(lb) 



S-A'-N-C0 2 R d 



40 



R c 



wherein A', R a , R c and R d are as defined above and X' is halogen, or a salt thereof. 

(H) A compound of the formula (1a) or a salt thereof is nitrosated to obtain a compound of the formula: 



45 



EP 0 471 236 A1 



70 



I NO 



(Id) 



S-A'-N-C0 2 R d 
i 

R c 

wherein A', R a , R c and R d are as defined above, or a salt thereof. 

(J) A compound of the formula (1c) or (1 d), or a salt thereof is reduced to obtain a compound of the 
formula: 



15 



20 



CO- 

S-A-N-C0 2 R d 



(le) 



25 



wherein A', R a , R c and R d are as defined above, or a salt thereof, or the compound (1e) or a salt thereof 
is further reacted with a compound (7) or a compound X'COR d (wherein X' and R d are as defined above) 
to obtain a compound of the formula: 



30 



35 




NH-R k 

S-A'- N- C0 2 R d 
i 

R c 



(If) 



40 



wherein R k is -C02R d or -COR d and A, R a , R c and R d are as defined above, or a salt thereof. 
(K) According to the following scheme, the compound (1g) or a salt thereof is obtained. 




wherein R 2a is a lower dialkylamino group or a cyclic amino group and A', R a , R c and R d are as defined 
55 above. 

The reaction of the compound (2) or a salt thereof with the compound (3) in the process A con be 
conducted at -10* C to +200*C in a solvent in the presence of a basic compound such as sodium 
hydroxide, potassium hydroxide, sodium hydride, potassium carbonate and the like by using 1 equivalent to 



76 

BNSDOCiD: <EP 0471236A1 I > 



EP 0 471 236 A1 



excess amount (but not interfering with the reaction) of the compound (3) per 1 equivalent of the 
compound (2) or a salt thereof. Examples of the solvent to be used include water; lower alcohols such as 
methanol, ethanol, propanol and the like; ketones such as acetone, methyl ethyl ketone and the like; ethers 
such as tetrahydrofuran and the like; aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfox- 
5 ide and the like. The reaction time is normally 1 hour to 2 days, preferably 1 to 8 hours. 

The reaction of the compound (4) or a salt thereof with the compound (5) in the process B is conducted 
under conditions similar to those of the reaction of the compound (2) with the compound (3) in the process 
A. 

The reaction of the compound (6) or a salt thereof with the compound (7) in the process C is conducted 
10 in a solvent at -30* C to + 200*C in the presence of an inorganic base such as portassium carbonate, 
sodium bicarbonate or the like or an organic base such as triethylamine, pyridine, dimethylanilin, 1,4- 
azabicyclo[2.2.2]octane (DABCO) or the like by using 1 equivalent to extremely excess amount of the 
compound (7) based on the compound (6) or a salt thereof. Examples of the solvent to be used include 
water; lower alcohols such as methanol, ethanol, propanol and the like; ketones such as acetone, methyl 
75 ethyl ketone and the like; ethers such as tetrahydrofuran and the like; aprotic polar solvents such as N,N- 
rlirnethylformamide, dimethylsijlfoxirfe and the like The reaction time is normally 10 minutes tn P4 hnurs. 
preferably 30 minutes to 6 hours. 

The reaction of the compound (8) or a salt thereof with the compound (9) in the process D can be 
conducted in a solvent at -30 to +20*C in the presence of a base such as potassium hydride, sodium 
20 hydride, sodium amide and the like by using 1 equivalent to extremely excess amount of the compound (9) 
based on the compound (8) or a salt thereof. Examples of the solvent to be used include ethers such as 
diethyl ether, tetrahydrofuran, dimethoxyethane and the like; aprotic polar solvents such as N.N-dimethylfor- 
mamide, dimethylsulfoxide and the like. The reaction time is normally 30 minutes to 24 hours, preferably 30 
minutes to 6 hours. 

25 The reaction of the compound (10) with the compound (11) in the process E can be conducted at -10 to 

+ 150* C in the absence or presence of a solvent by using 1 equivalent to extremely excess amount of the 
compound (11) based on the compound (10). Examples of the solvent to be used include ethers such as 
diethyl ether, tetrahydrofuran, dimethoxyethane and the like; halogenated hydrocarbons such as methylene 
chloride, chloroform, dichloroethane and the like; aprotic polar solvents such as N.N-dimethylformamide, 

30 dimethylsulfoxide and the like. In order to promote the reaction, a tertiary amine such as triethylamine, 
pyridine, dimethylaminopyridine, N-methylpiperidine or the like, or boron trifluoride ether (BF 3 *Et20) can be 
added. The reaction time is normally 30 minutes to 24 hours, preferably 30 minute to 6 hours. 

The reaction of the compound (12) or a salt thereof with the compound (11) in the process F can be 
conducted at -30 " C to +200* C in the absence or presence of a solvent by using 1 equivalent to extremely 

35 excess amount of the compound (11) based on the compound (12) or a salt thereof. Examples of the 
solvent to be used include ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane and the like; 
halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; aprotic 
polar solvents such as N,N-dimethylformamide, dimethylsulfoxide and the like. In order to promote the 
reaction, a tertiary amines such as triethylamine, pyridine, dimethylaminopyridine, N-methylpiperidine or the 

40 like may be added. The reaction time is normally 30 minutes to 24 hours, preferably 30 minutes to 6 hours. 

The reaction of the compound (1a) or a salt thereof with the halogenating agent in the process G can be 
conducted at -20 to +150*C in the absence or presence of a solvent by using 1 equivalent to extremely 
excess amount of the halogenating agent based on the compound (1a) or a salt thereof. Examples of the 
solvent to be used include halogenated hydrocarbons such as methylene chloride, chloroform, dich- 

45 loroethane, carbon tetrachloride and the like, acetic acid, propionic acid and the like. Examples of the 
hydrogenating agent include halogen molecules such as chlorine, bromine and the like; and N-halogenated 
succinimides such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like. Further, 



ntrattng agent based on the compound (1a) or a salt tnereof. Examples of tne solvent to be used include 
acetic acid, acetic anhydride, sulfuric acid and the like. As the nitrating agent, for example, there is fuming 
nitric acid, cone, nitric acid, mixed acid (nitric acid with sulfuric acid, phosphoric acid or acetic anhydride) 



EP 0 471 236 A1 



water; lower fatty acids such as acetic acid, propionic acid and the like; ethers such as tetrahydrofuran, 
dioxane and the like; aprotic polar solvents such as N.N-dimethyiformamide, dimethylsulfoxide and the like. 
As the nitrosating agent, for example, there are potassium nitrite, sodium nitrite and the like. The above 
reaction is conducted in the presence of an acid such as hydrochloric acid, sulfuric acid, phophoric acid, 

5 acetic acid or the like. The reaction time is normally 30 minutes to 1 day, preferably 30 minutes to 6 hours. 

The reduction of the compound (1c) or (1d) or a salt thereof in the process J can be conducted at -20 
to +200 C in the presence of a solvent by using 1 equivalent to extremely excess amount of a reducing 
agent based on the compound (1c) or (1d). Examples of the solvent to be used include water, methanol, 
ethanol, propanol, acetic acid and the like. As the reducing agent, for example, there is a mixture of iron and 

w hydrochloric acid, zinc and acetic acid and the like. Further, the reaction can also be conducted at -20 to 
+ 200 C in the presence of a solvent under atmospheric pressure of hydrogen by using a hydrogenation 
catalyst such as palladium black, palladium on carbon, raney-nickel or the like. The reaction time is 
normally 30 minutes to 2 days, preferably 1 to 12 hours. 

Further, the reaction of the compound (1e) or a salt thereof with the compound (7), or the reaction of the 

75 compound (1e) or a salt thereof with X'COR 4 is conducted under conditions similar to those of the reaction 
of the compound (6) or a salt thereof with the compound (7) in the process C. 

The Mannich reaction of the compound (1a) or a salt thereof with a lower dialkylamine and formalin, or 
cyclic amine and formal in in the process K can be conducted at -20 to + 10* C in the presence of a solvent 
by using 1 equivalent to extremely excess amount of a Mannich reagent based on the compound (1a) or a 

20 salt thereof. Examples of the solvent to be used include water; lower alcohols such as methanol, ethanol, 
propanol, isopropanol and the like; lower fatty acids such as acetic acid, propionic acid and the like. The 
reaction time is normally 30 minutes to 1 day, preferably 1 to 12 hours. 

In the above processes A to K, the compound which forms a salt may be used in the form of a salt and 
examples of such a salt include those described in the salt of the compound (1). 

25 In the starting material used in the processes A to K, for example, the compound (2) can be obtained by 

the following process. 



0 

n , 
R a -C-CH-R b 



35 




> (2 ) 



1 

X 

( 13 ) 

40 

The reaction of the compound (13) with the compound (14) can be conducted at 0 to +200* C in the 
absence or presence of a solvent by using 1 equivalent to extremely excess amount of the compound (14) 
based on the compound (13). Examples of the solvent to be used include water; lower alcohols such as 
methanol, ethanol, propanol and the like; ethers such as tetrahydrofuran, dimethoxyethane, dioxane and the 

45 like; nitriles such as acetonitrile, propionitrile and the like; aprotic polar solvents such as N,N-dimethylfor- 
mamide, dimethylsulfoxide and the like. Further, on the above reaction, an inorganic base such as 
potassium carbonate, sodium bicarbonate or the like, or an organic base such as triethylamine, pyridine, 
dimethylanilin or the like may be added as an acid-trapping agent. The reaction time is normally 10 minutes 
to 7 days, preferably 1 hour to 2 days. 

50 The compound (4) can be obtained, for example, by the following processes. 



55 



78 



BNSDOCID:<EP ... C471 236A1 J _> 



EP 0 471 236 A1 



( i ) 



YSH 

(2 ) > 




10 



wherein Y is sodium or potassium and R a and R b are as defined above 



75 



20 



(ii) 



HS 



Nfl : 



C 15 ) 



"> (4) 



25 



30 



35 



(iii) 




( 16 ) 

removal of 
protecting group 
> 



( 14 ) 



(4) 




40 wherein T is a protecting group such as p-methoxybenzyl, benzyl or the like and R a and R b are as defined 
above. 

The reaction of the compound (2) with YSH is conducted under conditions similar to those of the 
reaction of the compound (2) with the compound (3). 

The reaction of the compound (15) with the compound (14) is conducted under conditions similar to 
45 those of the above reaction of the compound (13) with the compound (14). 

The reaction of the compound (16) with the the compound (14) is conducted under conditions similar to 
those of the reaction of the compound (13) with the compound (14). 



EP 0 471 236 A1 



( i ) 



(2) 



HS-A'-<jj c 

( 18 ) 



10 



9* 

s-a-nCJc 

(6 ) 



wherein A\ R a , R b , R c and R d are as defined above. 



75 



Cii) 



20 



HS-A'-N(i; 



(2 ) 



( 19 ) 



25 



30 



removal of 
protecting group 

> 




(6) 



35 wherein T 1 is an amino protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl, trifluoroacetyl, 
trityl, benzyl or the like; and A', R a , R b and R c are as defined above. 



(in) 



40 



(4) 



X- A-N^ c 
( 21 ) 



> ( 20 ) 



45 



50 



removal of 
protecting group 
> (6 ) 

wherein A', ~P and R c are as defined above, but further including that -NT 1 R C is phthalimide. 



55 



80 

BNSDOCiD <EP 0471236A1 I ■, 



EP 0 471 236 A1 



10 



(iv) 



HS-A-OH 

(22 ) 
(2 ) > 



S- A'- OH 

( 23 ) 



R 3 



15 



conversion of OH 

1) into X 1 

2) R C NH 2 

( 24 ) 



(6) 



20 wherein A', R a , R b , R c , R d and X 1 are as defined above. 



(v) 



25 



X'-A'-NH 
i 

R c 

( 25 ) 
(4) > (6) 



30 



wherein X 1 and R c are as defined above. 



(vi) 



35 



40 




( 14 ) 



"> (20.) 



45 



removal of 
protecting group 
> 



(6) 



witn the compoouna (22) arc the reaction of the compound {4} witn the compound (25) are conducted 
under conditions similar to those cf the reaction of the compound (2) with the compound (3) in the above 
process A. 



EP 0 471 236 A1 



70 



methanesulfonyloxy group, it can be obtained by treating the compound (23) with toluenesulfonyl chloride or 
methanesulfonyl chloride. The subsequent reaction with the compound (24) is conducted at 0 to 200 "C in 
the absence or presence of a suitable solvent. All of these reactions are known and they can be conducted 
according to known conditions. 

The reaction of the compound (26) with the compound (14) is conducted under conditions similar to 
those of the above reaction of the compound (13) with the compound (14). 

The compound (10) is obtained, for example, by the following processes. 

(i) The compound (27) is reacted with phosgene and the reaction mixture is heated to conduct 
dehydrochlorination. 

(ii) The compound (28) is reacted with silver cyanate. 

All of these reactions are also known and they can be conducted according to known conditions. 



75 



20 



(i) 




( 27 ) 



1) 



Phosgene^ 



2) -HCf 



(10) 



25 wherein A', R a and R b are as defined above. 

(ii) 



30 



35 




( 28 ) 



AgOCN 



■> do) 



wherein A', R a and R b are as defined above. 

The compound (12) can be obtained, for example, by the following processes. 
40 (i) When X 2 is CI, the compound (6) is reacted with phosgene. 

(ii) When X 2 is phenoxy, the compound (6) is reacted with phenyl chlorocarbonate. 

(iii) When X 2 is imidazolyl, the compound (6) is reacted with carbonyldiimidazole. 

All of these reactions are known and they can be conducted according to known conditions. 

All of the reactions for removing the above protecting group are known and they can be conducted 
45 according to known conditions. For example, p-methoxybenzyl group as a protecting group of a mercapto 
group can be removed by treating with mercuric acetate in trifluoroacetic acid and treating with hydrogen 
sulfide or 2-mercaptoethanol. Benzyl group can be removed by sodium metal in liquid ammonia. 

For example, benzyloxycarbonyl group and benzyl group as protecting groups of amino group can be 
removed by conducting catalytic reduction (reaction temperature: 0 to 100 " C) in a solvent (e.g., alcohols, 
so acetic acid, water, tetrahydrofuran, a mixed solvent thereof, etc.) in the presence of a catalyst (e.g., 
palladium on carbon, platinum oxide, etc.). 

in the case of trityl group and tert-butoxycarbonyl group, they can be removed at 0 to 150* C in a 
solvent (e.g., water, alcohols, tetrahydrofuran, dioxane, etc.) in the presence of an acid (e.g., mineral acids 
such as hydrochloric acid, phophoric acid, sulfuric acid, etc.; organic acids such as toluenesulfonic acid, 
55 methanesulfonic acid, acetic acid, etc.). Trifluoroacetyl group can be readily removed by treating with an 
alkali (e.g., sodium hydroxide, sodium bicarbonate solution, etc.) 

Phthalimide group can be removed by treating with hydrazine hydrate in a solvent (e.g. methanol, 
ethanol, etc.). 



82 

6NSDOCID <EP 0471236A1 I > 



EP 0 471 236 A1 



The compounds (2), (4), (6), (10) and (12) can be isolated by the following conventional separation 
methods, but they may also be used in the form of a reaction mixture as a starting material for producing 
the desired compound (1) or a salt thereof Further, among the above compounds, the compounds (3), (5), 
(7), (13), (14), (18), (19). (21), (22), (24) and (25) can be produced, for example, according to the processes 

5 described in Shinzikken Kagaku Koza, Vol.14, "Synthesis and Reaction of Organic compounds l-V, Japan 
Chemical Society, published by Maruzen K.K., Tokyo; Shinzikken Kagaku Koza, Vol.15, "Oxidation and 
Reduction l-V", Japan Chemical Society, published by Maruzen K.K., Tokyo; "Organic Syntheses", John 
Wiley and Sons, Inc., New York; "Theilheimer's Synthetic Methods of Organic Chemistry", Basel, New York, 
Karger and the like or modification thereof. 

70 The isolation and purification of the compound (1) or a salt thereof from a reaction mixture is conducted 
according to conventional separation means (e.g. extraction, concentration, filtration, recrystallization, col- 
umn chromatography, thin layer chromatography, etc.). 

The compounds (1) or a salt thereof of the present invention have angiogenesis inhibitory activity and 
are useful as angiogenesis inhibitors, for example, antineoplastic agents, antiinflammatory agents, anti- 

is rheumatoid arthritis agents, anti-diabetic retinopathy agents and the like. 

The compound (1) or a salt thereof has low toxicity, and thprfifnra. it ran be orally or parenterally 
administered to mammal (e.g., human, rabbit, dog, cat, rat, mouse, guinea pig, etc.) as it is as a powder or 
a pharmaceutical composition in a suitable dosage form. The dosage varies depending upon a particular 
administration route, conditions to be treated, age, weight of the patient or the like. When the compound (1) 

20 or a salt thereof is used as an antineoplastic agent, such an agent can be obtained by admixing the 
compound (1) or a salt thereof with a pharmaceutical^ acceptable carrier. The compound (1) or a salt 
thereof can also be used by formulating it into a suitable dosage form such as instillations, injections, 
capsules, tablets, suppositories, solutions, emulsions, suspensions and other suitable dosage forms. 

When a dosage form for parenterally administration, for example, injection is produced, isotonicities 

25 (e.g., glucose, D-sorbitol, D-mannito!, sodium chloride, etc.), preservatives (e.g., benzyl alcohol, 
chlorobutanol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, etc.), anticoagulants (e.g., dextran 
sulfuric acid, heparin, etc.) and buffer agents (e.g., phophoric acid buffer, sodium acetate buffer, etc.) may 
be used. Further, a dosage form for oral administration can be used as capsules wherein the compound (1) 
or a salt thereof is admixed with lactose and the like, or used as sugar-coated tablets produced by a 

30 conventional method. 

For example, in the case of administering the compound (1) or a salt thereof parenterally by injection to 
the diseased part (s.c, i.v. or i.m ), the dosage may be about 0.05 to 50 mg/kg/day. preferably about 0.2 to 
20 mg/kg/day, more preferably about 0.5 to 10 mg/kg/day. In the case of oral administration, the dosage 
may be about 0.1 to 500 mg/kg/day, preferably about 1 to 100 mg/kg/day, more preferably 5 to 50 

35 mg/kg/day. Further, the compound (1) or a salt thereof can be used for topical application. For example, by 
washing a diseased part of the body such as head, breast, abdomen, limb and the like with a solution 
wherein the compound (1) or a salt thereof is dissolved in an isotonic solution in a concentration of about 
0.01 to 2 w/v %, or by applying an ointment containing the compound (1) or a salt thereof in an amount of 
about 0.1 to 50 mg/l g to the above diseased part, the compound (1) of a salt thereof can be used for 

40 preventing and treating tumor of these parts. 

As described hereinabove, anangiogenesis inhibitory composition comprising the compound (1) and a 
salt thereof of the present invention have excellent activity and, in view of this activity, they are useful as 
medicines for prevention and treatment of tumor, rheumatoid arthritis and the like of human and mammal. 
The following Reference Examples, Examples, Preparations and Experiments further illustrate this 

45 aspect of the present invention in detail but are not to be construed to limit the scope thereof. In the 
Reference Examples, Examples and Preparations, "room temperature" is 15 to 25* C. 



To a solution of 5-(2-nydroxy)ethy lrhioimidazo[ 1 ,2-ajpyrdme (9.71 g. SO mmoies; anc tnotr ylamtno 
(10.5 ml. 75.3 mmoles) in methylene chloride (300 ml) was added methanesulfony! chloride (4.26 ml. 55 
mmoles) under ice-cooling with stirring and the mi<ture was stirred under ice-cooling for 2 hours. The 

r- \1 c fpn-p \1M.- C?0 ? po- 3 ?c • - n 4H/ . *: 35 f?h : = 4h; 7 (-8 ' 1 m 77. 7=/ 



EP 0 471 236 A1 



1.2Hz), 7.18 (1H, dd, J = 8.8, 7Hz), 7.64 (1H, m), 7.73 (1H, d, J = 1.4Hz), 7.91 (1H, m) 
Reference Example 2' 

(1) Synthesis of 5-[2-(methylamino)ethylthio]imidazo[1 ,2-a]pyridine 

A solution of 5-[2-(methylsulfonyloxy)etylthio]imidazo[1,2-a]pyridine (2.18 g, 8 mmoles), triethylamine 
(2.24 ml, 16 mmoles) and a 40% methylamine-methanol solution (20 ml) in chloroform (20 ml) was heated 
at reflux for 3 hours. The reaction mixture was washed with 3N NaOH and dried over anhydrous magnesium 
sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent: 
methanol/chloroform (1:10)] to obtain 781 mg of the desired product (47.1%, light brown oily product) 
NMR (200MHz, CDCI3) 6: 2.31 (1H, br), 2.88 (2H, t, J = 6.4Hz), 3.16 (2H, t, J = 6.4Hz), 6 94 (1H dd J = 7 
1Hz). 7.15 (1H, dd, J = 9, 7Hz), 7.58 (1H, dd, J = 9, 1 Hz), 7.69 (1 H, d, J = 1.2Hz) 
IR (KBr) cm" 1 : 3290, 3105, 2930, 2850, 2790, 1655, 1615, 1530, 1490 

According to the same manner as that described in Reference Example 2' (1), the following compound 
was obtained. 

(2) 5-[2-(Ethylamino)ethylthio]imidazo[1 ,2-a]pyridine 

NMR (200MHz f CDCI3) 5: 1.11 <3H, t, J=7Hz), 1.88 (1H, br), 2.70 (2H, m), 2.90 (2H, t, J = 6.2Hz) 3 15 (2H 
t, J=6.2Hz), 6.94 (1H, dd, J = 7, 1Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.59 (1H, dd, J=9, 1Hz) 7 70 (1H d' 
J = 1 .2Hz), 7.87 (1 H, s) ' ' 

IR (KBr) cm' 1 : 3280, 3105, 2965, 2930, 2890, 2820, 1655, 1620, 1530, 1490 

Reference Example 3' 

(1) Synthesis of 5-[2-(amino)ethylthio]imidazo[1 ,2-a]pyridine 

After a suspension of 5-[2-(amino)ethylthio]imidazo-[1 ,2-a]pyridine dihydrochloride (13.31 g, 50 mmloes) 
in chloroform (200 ml) was washed with 3N sodium hydroxide (50 ml), the aqueous layer was extracted with 
chloroform, the combined chloroform layer was dried over anhydrous magnesium sulfate. Then, the solvent 
was distilled off to obtain 9.63 g of the desired product (99.7%, pale yellow oily product). 
NMR (200MHz, CDCI3) 5: 1.67 (2H, br), 2.95 (2H, m), 3.08 (2H, m), 6.95 (1H, d, J=7Hz) 7 15 (1 H dd 
J = 9.2, 7Hz), 7.59 (1 H, d, J = 9.2Hz), 7.71 (1 H, s), 7.88 (1 H, s) 

Reference Example 4' 

Synthesis of 5-[3-(amino)propylthio]imidazo[1 ,2-a]pyridine 

To a mixed solution of 10% (w/w) potassium hydroxide (69.3 g, 105 mmoles) and dimethylsulfoxide (50 
ml) was added S-(3-aminopropyl)isothiourea dihydrobromide (8.85 g, 39 mmoles) and the mixture was 
stirred at room temperature for 1.5 hours. To the reaction mixture was added 5-chloroimidazo[1 ,2-a)pyridine 
(3.05 g, 20 mmoles), followed by stirring at room temperature and additionally at 65* C for 20 hours. Water 
was added to the reaction mixture, which was extracted with chloroform, washed with 1N sodium hydroxide 
several times and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to obtain 2.66 
g of the desired product (64.3%, pale yellow oily product). 

NMR (200MHz, CDCI3) 5: 1.29 (2H, br), 1.80 (2H, m), 2.85 (2H, t, J=6.8Hz), 3.08 (2H, t, J = 72Hz) 6 91 (1H 
dd, J=7, 1Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.58 (1H, d, J = 9, 1Hz), 7.71 (1H, d, J » 1.2Hz) 7 85 (1H d' 
J = 1.2Hz) ' ' 

Example 1' 

(1) Synthesis of 5-[2-(methoxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound V) 

To a solution of 5-[2-(amino)ethylthio]imidazo[1 ,2 a]pyridine (1.93 g, 10 mmoles) and triethylamine (1.53 
ml, 11 mmoles) in methylene chloride (30 ml) was added methyl chloroformate (0.77 ml, 10 mmoles) under 
ice-cooling with stirring and the mixture was stirred at room temperature for 20 minutes. The reaction 
mixture was washed in turn with aqueous sodium bicarbonate and water and dried over anhydrous 



84 



EP 0 471 236 A1 



magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography 
[eluent: ethanol/ethylacetate (1:10)] to obtain 1.68 g of the desired product (66.9%, colorless crystals). 
Melting point: 1 98-200.0 "C 



5 


Elemental analysis for Ci 1 hh 3N 


3 0 2 S, 




Calcd.: 


C, 52.57; 


H, 5.21; 


N, 16.72 




Found : 


C, 52.68; 


H, 5.22; 


N, 16.60 



10 NMR (200MHz, CDCI3) 5: 3.12 (2H. m). 3.40 (2H, m), 3.68 (3H, s), 5.10 (1H, br), 7.00 (1H, d, J = 7Hz), 7.16 
(1H, dd, J = 9, 7Hz), 7.61 (1H, d, J = 9Hz), 7.72 (1H, s), 7.87 (1H, s) 

According to the same manner as that described in Example V (1), the following compounds were 
obtained. 



(2) 5-[2-(Ethoxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 2*) 
Melting point. 68-70' C 



20 


Elemental analysis for C12H15N3O2S, 




Calcd.: 


C, 54.32; 


H, 5.70; 


N, 15.84 




Found : 


C, 54.33; 


H, 5.75; 


N, 15.83 



25 

(3) 5-[2-(Propyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 3') 
Melting point: 62-64* C 



30 


Elemental analysis for C13HWN3O2S, 




Calcd.: 


C, 55.89; 


H, 6.13; 


N, 15.04 




Found : 


C, 55.87; 


H, 6.09; 


N, 14.96 



NMR (200MHz, CDCI3) S: 0.92 (3H, t, J = 7.4Hz), 1.62 (2H, m). 3.14 (2H, t, J = 6.6Hz), 3.42 (1 H, m), 4.01 (1H, 
t, J = 6.6Hz), 5.07 (1H, br), 7.02 (1H, d, J = 7Hz), 7.17 (1H, dd, J = 9, 7Hz), 7.60 (1H, d, J = 9Hz), 7.71 (1 H, d. 
J= 1.2Hz), 7.86 (1H, s) 

IR (KBr) cm" 1 : 3210, 3025, 2965, 1695, 1620, 1545, 1490, 1275 

(4) 5-[2-(Butyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 4') 

Melting point: 75-76* C 



45 



Elemental analysis for Ci 4^3^028, 



Calcd.. 
Found 



C, 57.31; 
C, 57.32; 



H, 6.53; 
H, 6.55; 



N, 14.32 
N, 14.23 



t.tib ( 1 H, S; 

IR (KBr) crrr 1 : 3490, 3210, 2970, 1695, 1615, 1500, 1285 



EP 0 471 236 A1 



Elemental analysis for Ci 3^7^028, 


Calcd.: 
Found : 


C, 55.89; 
C, 55.85; 


H, 6.13; 
H. 6.14; 


N, 15.04 
N, 14.96 



NMR (200Hz. CDCI 3 ) 5: 1.22 (6H, d, J=6.2Hz), 3.14 (2H, t, J = 6.4Hz), 3.41 (2H, m), 4.94 (1H, br), 7.02 (1H, 
d, J = 7Hz), 7.17 (1H, dd, J = 9, 7Hz), 7.61 (1H, d, J = 9, 7Hz), 7.71 (1 H, d, J = 1.4Hz), 7.86 (1H, s) 
IR (KBr) cm" 1 : 3220, 3025, 2970, 1705, 1630, 1545, 1300, 1240 

(6) 5-[2-(lsobutyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 6') 

Melting point: 75*76* C 



75 


Elemental analysis for C14H19N3O2S, 




Calcd.: 


C, 57.31; 


H, 6.53; 


N, 14.32 




Found : 


C, 57.29; 


H, 6.53; 


N, 14.41 



20 NMR (200Hz, CDCI3) 5: 0.91 (6H, d, J = 6.8Hz), 1.89 (1H, m), 3.14 (2H, t, J - 6.4Hz), 3.42 (2H, m), 3.84 (2H, 
t, J = 6.6Hz), 5.15 (1H, br), 7.01 (1H, dd, J = 7Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.59 (1H, d, J = 9Hz), 7.70 (1H, 
d, J = 1.2Hz), 7.85 (1H, s) 

(7) 5-[2-{Allyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 7') 

25 

Melting point: 72.5-73.5* C 





Elemental analysis for C13H15N3O2S, 


30 


Calcd.: 


C, 56.30; 


H, 5.45; 


N, 15.15 




Found : 


C, 56.34; 


H, 5.44; 


N, 15.04 



NMR (200Hz, CDCI3) 5: 3.15 (2H, t, J=6.4Hz), 3.43 (2H, m), 4.56 (2H, m), 5.07 (1H, br), 5.18-5.36 (2H, m), 
5.90 (1H, m), 7.02 (1H, d, J = 7Hz), 7.17 (1H, dd, J = 9, 7Hz), 7.61 (1 H, d, J = 9Hz), 7.72 (1H, d, J = 1.4Hz), 
7.86 (1H, m) 

IR (KBr) cm" 1 : 3205, 3020, 1700, 1625, 1570, 1490, 1270 

(8) 5-[2-[2,2,2-(Trichloro)ethoxycarbonylamino]ethylthio]imidazo[1,2-a]pyridine (Compound 8') 
Melting point: 1 13.0-1 14.0* C 



Elemental analysis for C12H12N3O2SCI3, 


Calcd.: 
Found : 


C, 39.10; 
C, 39.23; 


H, 3.28; 
H, 3.27; 


N, 11.4 
N, 11.25 



NMR (200Hz, CDCI3) 5: 3.17 (2H, t, J = 6.4Hz), 3.48 (2H, m), 4.73 (2H, s), 5.52 (1H, br), 7.03 (1H, d, 
J = 7Hz), 7.1 7 (1 H, dd, J = 9, 7Hz), 7.62 (1 H, d, J = 9Hz), 7.71 (1 H, d, J = 1 .2Hz), 7.87 (1 H, m) 
50 IR (KBr) cm" 1 : 3195, 2975, 1725, 1615, 1545, 1485, 1260, 1210 

(9) 5-[2-(Benzyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 9*) 

Melting point: 52.0-53.0* C 

55 



86 

3NSDOCID- <EP 0471236A1 I > 



EP 0 471 236 A1 



Elemental analysis for C17H17N3O2S, 


Calcd.: 
Found : 


C, 62.36; 
C, 62.34; 


H, 5.23; 
H, 5.22; 


N, 12.83 
N, 12.75 



NMR (200Hz, CDCl 3 ) 5: 3.14 (2H, t, J = 6.4Hz), 3.43 (2H, m), 5.09 (2H, s), 5.17 (1H, br), 6.99 (1H, d, 
J = 6.8Hz), 7.13 (1H, dd, J =9.2, 6.8Hz), 7.35 <5H, s), 7.59 (1H, d, J = 9.2Hz), 7.69 (1H, s), 7.84 (1H, s) 

(10) 5-[2-[(9-Fluorenyl)methyloxycarbonylamino]ethylthio]imidazo[1 ,2-a]pyridine (Compound 10') 

Melting point: 105.0-108.0* C 



Elemental analysis for C 24 H 21 N 3 O 2 S # 0.4H 2 O, 


Calcd.: 
Fuunu : 


C, 69.07; 
C, 69. 1 4; 


H, 5.05; 
H, 5.23; 


N, 9.67 
in, 9.96 



NMR (200MHz, CDCb) 5: 3.13 (2H, t, J = 6Hz), 3.42 (2H, m), 4.21 (1H, t, J = 6.6Hz), 4.43 (2H, d, J = 6.6Hz), 
5.17 (1H, br), 7.01 (1H, d, J = 7.4Hz), 7.15 (1 H, dd, J =8.6, 7.4Hz), 7.29-7.46 (4H, m), 7.53-7.65 (3H, m), 
7.60-7.87 (4H, m) 

IR (KBr) cm' 1 : 3205, 3020, 1710, 1625, 1550, 1485, 1450, 1270 

(11) 5-[2-(Phenoxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine (Compound 1V) 

Melting point: 96.0-97.0* C 



Elemental analysis for Ci&Hi 5 N 3 0 2 S, 


Calcd.: 
Found : 


C, 61.32; 
C, 61.35; 


H, 4.82; 
H, 4.86; 


N, 13.41 
N, 13.30 



IR (KBr) cm~': 3200, 3005, 1725, 1615, 1555, 1485, 1270, 1210 

(12) 5-[2-(N-Methyi-N-isopropy!oxycarbonylamino)ethythio]imidazo[1 ,2-a]pyridine (Compound 12*) 

NMR (200MHz, CDCb) 5: 1.02-1.35 (6H, m), 2.91 (3H, s), 3.05-3.26 (2H, m), 3.38-3.60 (2H, m), 4.89 (1 H, m), 
7.01 (1H, br), 7.18 (1H, dd, J = 9, 7Hz), 7.60 (1H, d, J = 9Hz), 7.71 (1H, s), 7.84 (1H, s) 
IR (KBr) cm" 1 : 3220, 3025. 2970, 1705, 1630, 1545 

(13) 5-[2-(N-Ethyl-N-isopropyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 13') 

NMR (200MHz, CDCI 3 ) 6: 0.95-1.35 (9H, m), 3.02-3.68 (6H, m), 4.90 (1H, m), 7.04 (1H, m), 7.19 (1 H, dd, 
J = 9, 7Hz), 7.60 (1 H, d, J = 9Hz), 7.72 (1 H, s). 7.83 (1 H, s) 
IR (KBr) cm" 1 : 3220, 3025, 2970, 1705, 1630, 1545 

(14) 5-[3-(Methoxycarbonylamino)propylthio]imidazo[1 ,2-a]pyridine (Compound 14') 



mertai analysis 'of u- ;/h< NjO^b. 



Calcd. : 
Found 



C, 54.32; 
C. 54.48: 



H, 5.70; 
H, 5.74; 



N, 15 84 
N. 15 72 



EP 0 471 236 A1 



(15) 5-[3-(isopropyloxycarbonylamino)propylthio]imidazo[1 ,2-a]pyridine (Compound 15') 

NMR (200MHz, CDCb) 6: 1.22 (6H, d, J = 6.2Hz), 1.85 (2H, m), 3.03 (2H, m), 3.31 (2H, m), 4.82 (1H, br), 
4.90 (1H, heptet, J = 6.2Hz), 6.90 (1 H, dd, J=7, 1Hz), 7.15 (1H, dd, J = 9, 7Hz), 7.57 (1H, m), 7.69 (1H, d. 
5 J = 1.4Hz), 7.84 (1H, m) 

IR (KBr) cm" 1 : 3210, 3025, 2965, 1695, 1620, 1545, 1490, 1275 

(16) 5-[1-(tert-Butoxycarbonyl)-4-piperidylthio]imidazo[1 ,2-a]pyridine (Compound 16*) 

w NMR (200MHz, CDCI 3 ) 6: 1.45 (9H, s), 1.50-1.98 (4H, m). 2.90 (2H, m), 3.36 (1H, m), 3.98 (2H, m), 7.03 (1H, 
dd, J = 7, 1.2Hz), 7.15 (1H, dd, J = 9, 7Hz), 7.64 (1H, m). 7.70 (1H, d, J= 1.2Hz), 7.96 (1H, m) 

(17) 5-[1-(lsopropyloxycarbonyl)-4-piperidylthio]imidazo[1 ,2-a]pyridine (Compound 17') 

75 NMR (200MHz, CDCb) 5: 1.23 (6H, d, J = 6.2Hz), 1.50-1.98 (4H, m), 2.94 (2H, m), 3.37 (1H, m), 4.03 (2H, 
m), 4.91 (1H, heptet, J = 6.2Hz), 7.03 (1H, dd, J = 7, 1.2Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.65 (1H, d, J = 9Hz), 
7.71 (1H, d, J = 1.2Hz), 7.97 (1H, s) 

Example 2' 

20 

(1) Synthesis of 3-bromo-5-t2-(isopropyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (Compound 18') 

To a solution of 5-[2-(isopropyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (279 mg, 1 mmole) in 
chloroform (5 ml) was added N-bromosuccinimide (187 ml, 1.05 mmoles) and the mixture was stirred at 
25 room temperature for 1 hour. The reaction solution was washed with water and dried over anhydrous 
magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography 
(eluent: ethyl acetate) to obtain 296 mg of the desired product (82.7%, colorless solid). 
Melting point: 103.0-104.0" C 



30 


Elemental analysis for Ci 3 Hi 6 N 3 02SBr, 




Calcd.: 


C, 43.58; 


H, 4.50; 


N, 11.73 




Found : 


C, 43.60; 


H, 4.53; 


N, 11.74 



NMR (200MHz, CDCI 3 ) 6: 1 22 (6H, d, J = 6.2Hz), 3.11 (2H, t, J = 6.6Hz), 3.42 (2H, m), 4.90 (1H, heptet, 
J = 6.2Hz), 4.96 (1H, br), 7.00 (1H, dd, J = 7, 1.2Hz), 7.14 (1H, dd, J = 8.8, 7Hz), 7.57 (1H, dd, J =8.8, 1.2Hz), 
7.59 (1H, s) 

According to the same manner as that described in Example 2' (1), the following compound was 
obtained. 

(2) 3-Chloro-5-[2-(isopropyloxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine (Compound 19') 
Melting point: 1 1 3.0-1 14.0 " C 



Elemental analysis for Ci3HuN3O2SCI # 0.2H2O, 



Calcd.: 


C, 49.19; 


H, 5.21; 


N, 13.24 


Found : 


C, 49.38; 


H, 5.26; 


N, 13.22 



50 

NMR (200Hz, CDCb) 5: 1.22 (6H, d, J = 6.4Hz), 3.12 (2H, t, J = 6.4Hz), 3.43 (2H, m), 4.90 (1H, heptet, 

J = 6.4Hz), 4.96 (1H, br), 6.99 (1H, dd, J = 7.2, 1.2Hz), 7.10 (1H, dd, J = 8.8, 7.2Hz), 7.53 (1H, dd, J = 8.8, 
1.2Hz), 7.54 (1H, s) 

55 Example 3' 

(1 ) Synthesis of 5-[2-(isopropyloxycarbonylamino)ethylthio]-3-morpholinomethylimidazo[1 ,2-a]pyridine 
(Compound 20') 

88 

BNSDOCIO: <EP. . 0471 236A"" J . > 



EP 0 471 236 A1 



To a solution of an aqueous 37% formalin solution (210 mg, 2.59 mmoles) in acetic acid (2 ml) was 
added morpholine (226 ul, 2.59 mmoles) under ice-cooling and the mixture was stirred at room temperature 
for 45 minutes. 5-[2-(isopropyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (651 mg, 2.33 mmoles) 
was added, followed by stirring at 60 * C for 2 hours. After the solvent was distilled off, the residue was 
5 diluted with chloroform, washed in turn with aqueous 1N NaOH and saturated saline, and then dried over 
anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column 
chromatography [eluent: ethanol/ethy! acetate = 1:10] to obtain 442 mg of the desired product (50.1%, light 
brown solid). 

NMR (200MHz, CDCb) 5: 0.96 (6H, d, J = 6.2Hz), 2.56 (4H, m), 3.26 (2H, m), 3.36 (2H, m), 3.69 (4H, m), 
70 4.10 (2H, s), 4.59 (1H, heptet, J = 6.2Hz), 6.85 (1H, br), 7.01 (1H, d. J = 5Hz), 7.13 (1H, dd, J = 8.6. 6.6Hz), 
7.51 (1 H, s), 7.53 (1 H, d, J = 8.6Hz) 

Example 4' 



75 Synthesis of 5-[2-(isopropyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine hydrochloride (Compound 
21') 

A solution of 5*[2-(isopropyloxycarbonylamino)ethylthio]imidazo[1 ,2-a]pyridine (279 mg, 1 mmoles) in 
methanol (10 ml) was treated with hydrogen chloride-methanol. After the solvent was distilled off, the 
20 residue was crystallized from isopropanol-ethyl acetate-methanol. The crystals thus obtained were washed 
with water and dried to obtain 290 mg of the desired product (92.1%, colorless crystals). 
Melting point: 145-150* C 



Elemental analysis for C13H17N3O2 


s- 


HCI, 


Calcd.: 


C, 49.44; 


H, 5.74; 




N, 13.30 


Found : 


C, 49.51; 


H, 5.64; 




N, 13.14 



Example 5' 



Synthesis of 5-[4-(isopropyloxycarbonylamino)butylthio]imidazo[1 ,2-a]pyridine (Compound 22') 

To 5-(4-amino)butylthioirmidazo[1 ,2-a]pyridine (370 mg, 1.67 mmoles) and triethylamine (0.35 ml, 2.51 
mmoles) in methylene chloride (20 ml) was added isopropyl chloroformate (0.25 g. 2.04 mmoles) under ice- 
cooling with stirring and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was 
washed in turn with aqueous saturated sodium bicarbonate and saturated saline, and then dried over 
anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column 
chromatography (eluent: ethyl acetate) to obtain 215 mg of the desired product (41.8%, light tan oily 
product). 

NMR (200MHz, CDCb) 5: 1.22 (6H, d, J = 6.2Hz), 1.54-1.72 (4H, m), 3.02 (2H, m), 3.18 (2H, m), 4.66 (1H, 
br), 4.90 (1H, heptet, J = 6.2Hz), 6.90 (1H, dd, J = 7, 1Hz), 7.15 (1H, dd, J = 9, 7Hz), 7.58 (1H, d, J = 9Hz), 
7.70 (1H, m), 7.84 (1H, m) 

Preparation 1* 



i-ti LarOuxymui'"/ uiCi.^ ..u .\.r. 


44 y 


(5) Magnesium stearate 


1 g 


1000 Tablet 


2l0g 







4. ; : - 



EP 0 471 236 A1 



10 



75 



mg of the component (1) per one tablet. 
Preparation 2' 

An ointment was prepared by uniformly kneading the following components. 

Compound 5 1 
Liquid paraffin 
White petrolatum 
Total amount 

Preparation 3' 



0.5 g 

i g 

sui table amount 
100 g 



20 



(1) Compound 5* 


1 9 


(2) Cacao fat 


19 g 



All the components (1) and (2) were kneaded on a water bath at about 60 " C. Then, the mix was 
25 charged in a suppository mold and cooled to produce 10 suppositories, each containing 2 g of the mixture. 

Preparation 4' 



30 



35 



(1) Compound 5* 


10 g 


(2) Lactose 


4.5 g 


(3) Corn starch 


4.5 g 


(4) Magnesium stearate 


1 9 


1000 capsules 


20 g 



All the components were thoroughly admixed and the mixture was filled in a suitable gelatin capsule to 
produce 100 capusules containing 100 mg of the component (1) per one capsule. 

40 Preparation 5' 

An injection prepartion filled in an ampoule was prepared by admixing and dissolving the following 
components. 



45 



50 



per one ampoule 
Compound 21' 50 mg 

Sodium chloride 18 mg 

Distilled water for injection suitaole amount 
Total amount 2 ml 



55 



Experiment V 



90 



BMSDOCID: <EP_ 0471236A1 I > 



EP 0 471 236 A1 



Effect of the desired compound on growth of endothelial cells 



This experiment was conducted by using endothelial cells (HUVE cells) obtained from human umbilical 
vein. 2 x 10 3 HUVE cells were suspended in a complete medium prepared by adding 2.5% FBS (fetal 
5 bovine serum) to GIT medium (manufactured by Nihon Seiyaku K.K.). Then, the suspension was distributed 
in a 96-well microtiter plate, which was cultivated at 37* C in an atmosphere of 5% carbon dioxide-7% 
oxygen-88 % nitrogen. After 24 hours, human recombinant basic FGF (endotherial cell growth factor) was 
added thereto in the final concentration of 2 ng/ml and a test compound was further added, followed by 
cultivation for 3 days. After cultivation, growth rate of HUVE cells was measured by MTT method [Cancer 
10 Treatment Reports, Vol. 71, page 1141-1149, 1987]. 

The test compounds inhibited growth of human umbilical endothelial cells. 

ICso value (the concentration of the test compound inhibiting growth of endothelial cells by 50%) of the 
test compound was determined from a graph of growth curve of HUVE cells. The results are shown in Table 
V. 

75 

Table 1* 



Test compound 


ICso (uM) 


V 


18 


2' 


7 


3' 


27 


5' 


4 


T 


29 


8' 


12 


10* 


43 


18' 


20 


19' 


6 


2V 


5 



30 

As shown in Table 1', the compounds of the present invention have excellent inhibitory activity of 
endothelial cells growth. 



^ Experiment 2' 

Effect of the desired compound on growth of bovine artery endothelial cells 



This experiment was conducted by using endothelial cells (BAE cells) derived from bovine aorta. 5 x 
10 3 BAE cells were suspended in a complete medium prepared by adding 5% FBS (fetal bovine serum) to 
Dulbecco's modified Eagle's minimum essential medium (D-MEM medium). Then, the suspension was 
distributed in a 96-well microtiter plate, which was cultivated at 37 *C in an atmosphere of 5% carbon 
dioxide-95% air. After 24 hours, human recombinant basic FGF (endothelial cell growth factor) was added 
thereto in the final concentration of 2 ng/ml and a test compound was further added, followed by cultivation 
for 3 days. After cultivation, growth rate of BAE cells was measured by MTT method [Cancer Treatment 
Reports, Vol. 71, page 1141-1149, 1987]. 

The test compounds inhibited growth of bovine artery endothelial cells. 

IC^c value (the concentration of the test compound inhibiting growth of endothelial cells by 50%) of 



Effect of the desrec compound on growto of human umbilica: vein endothelial cells by phorool ester 

This evoc'me n t was courted by usino endothelial eel's (HUVE ce ! 's) obtained from human u^b'Hca' 



EP 0 471 236 A1 



final concentration of 1 nM and a test compound was added, followed by cultivation for 3 days. After 
cultivation, growth rate of HUVE cells was measured by MTT method [Cancer Treatment Reports, Vol. 71, 
page 1141-1149, 1987]. 

The test compounds inhibited growth of human umbilical endothelial cells by phorbol ester, 
s IC50 value (the concentration of the test compond inhibiting growth of endothelial cells by 50%) of 

Compound 1 was 15 uM. 

Experiment 4' 



70 Effect of the desired compound on inhibition of increase in intracellular calcium concentration by phorbol 
ester 

Bovine aorta endothelial cells (BAE cells) were cultivated on a cover glass loaded with 4 uM Flar 2 
(manufactured by Dojin Kagaku Kenkyusho) and inserted into a quartz cuvette containing 2.5 ml of HEPES 
75 buffer (pH 7.5). 

The quartz cuvette was fixed so that the cover glass was positioned on the diagonal side at angles of 
45* to the incident direction of an excited light. 

Fluormetry was conducted with a spectrophotofluorometer F-4000 (manufactured by Hitachi Seisakusho 
K.K.). Excitation was obtained at 340 nm and 380 nm and fluorescence of 505 nm was recorded. 
20 Fmax was determined by lonomicine (2 uM, manufactured by Carbairochen Co.) which was a calcium 

ionophore and Fmin was determined by EGTA (8 mM) which was a chelating agent of calcium ion. 

Intracellular calcium ion concentration [Ca ]i was calculated by the following formula: 

[Ca**]i = Kd x (R - Rmin) x Sf 2 /(Rmax - R) x Sb 2 
25 R = {D (Wi) - AutoFi}/{D (W 2 ) - AutoF 2 } 

wherein D (Wi): a measured value of excited wavelength Wt ; D (W 2 ): a measured value of excited 
wavelength W 2 ; AutoFi : autofluorescence at Wi ; AutoF 2 : autofluorescence at W 2 ; Rmin: R (Ca** = 0) = 
Fmin (Wi)/Fmin (W 2 ); Rmax: R (saturated Ca + * concentration) = Fmax (W^/Fmax (W 2 ); Sf 2 : fluorescence 
30 intensity in a free state at W 2 ; Sb 2 : fluorescence intensity in Ca** bound state at W 2> which was obtained 
by correcting the formula of Zehn et al.: 

[Ca**]i = Kd x (F - Fmin)/(Fmax - F) 

35 by taking Kd as 224 nM. 

The experiment was conducted by adding a test compound at various concentrations to a solution in a 
cuvette and incubated for 5 minutes. Then, 12-O-tetradecanoylphorbol 13-acetate (TPA) of 2 nM in the final 
concentration was added and change of fluorescence intensity was observed. 

It was found that the test compounds inhibited increase in intracellular calcium concentration by phorbol 
40 ester (TPA). 

Change of inhibitory activity due to change of the concentration of Compound V is shown in Table 2*. 

Table 2* 



Effect of Compound 1 ' on inhibition of increase in intracellular 


calcium concentration by phorbol ester 


Concentration of Compond (M) 


Inhibitory activity (%) 


8 x 10"6 


100 


8 x 10" 7 


88 


8 x 10" 8 


81 



55 Claims 

1. A calmodulin inhibitory composition comprising a compound of the formula (I): 



92 

B.NSDOCIC <E D _0-a^i236A1_I_ > 



EP 0 471 236 A1 




(I) 



X-A-B 



70 wherein X is S, S(O), S(0) 2 , O or NR 3 (wherein R 3 is a hydrogen or an optionally substituted 

hydrocarbon group); A is a divalent straight or branched Ci-is hydrocarbon group which may contain 
an ethereal oxygen at any possible position and may have a substituent at a branched part of the 
hydrocarbon group; B is an acylated amino group or an acylated or etherified hydroxyl group and the 
nitrogen atom of the amino group of B may form a ring together with the carbon atom of A or R 3 ; and 

75 R 1 and R 2 are the same or different and are a hydrogen, an optionally substituted hydrocarbon group, a 

halogen, a nitro group, a nitroso group, an optionally protected amino group, a lower alkoxycarbonyl 
group or a lower alkylcarbamoyl group, or a pharmaceutical^ acceptable salt or solvate thereof, and a 
pharmaceutical^ acceptable carrier, diluent or excipient. 

20 2. A calmodulin inhibitory composition according to claim 1, wherein 

each optionally substituted hydrocarbon group of R 1 and R 2 is independently Ci-& alkyl, phenyl- 
Ci-& alkyl, naphthyl-d-6 alkyl or aryl, which may have 1 to 4 substituents; 

optionally substituted hydrocarbon group of R 3 is C1 - 6 alkyl, phenyl-Ci- 6 alkyl or naphthyl-Ci 
alkyl, which may have 1 to 4 substituents; 
25 A is (a) a group of the formula: 



30 



■(C) 1 "|C) B -{C) n - 



(wherein I, m and n are integers of 0 to 5, respectively; and each of R*. R 5 , R 6 , R 7 , R 8 and R 9 is 
35 independently (1) hydrogen, or (2) Ci- G alkyl, C2-6 alkenyl, phenyl-Ci - 6 alkyl, naphthyl-Ci - 6 alkyl 

or C*-24 aryl, which may have 1 to 4 substituents, or R* and R 5 or R 6 and R 7 or R 8 and R 9 may 
bind to each other to form a ring, or R* or R 6 may bind to R 8 or R 9 , respectively, to form a ring), 

(b) a group of the formula: -CH 2 CH 2 OChbCH 2 - or 

(c) a group of the formula: 



40 



45 



/n* (ch 2 )p- 

-(CH 2 )o-^J 



(wherein o and p are integers of 0 to 5); 
B is (a) a group of the formula: 



I; <cy Nycro^^i uu*. grojj< m p jJ Ly :,jl ng b K. o rnomL»o*uu r;r.ys. aikeny . f.-"0'iy i-L ■ -- 

alkyi, naphthy'-C- -& alkyl or d aryl, which may have 1 to 4 substituents, or (3) a member 
selected from the group consisting of -CO-R i: , -S0 2 R ,3 ) -CO-NR M R : " and -CS-NR' 4 W ; R' 1 is -CO- 



EP 0 471 236 A1 



70 



75 



20 



25 



30 



35 



40 



45 



50 



(wherein R 18 is (1) Ci -30 straight or branched alkyl, Cj-s cycloalkyl, saturated bi- or tricyclic 
hydrocarbon group formed by fusing 5 to 8 membered rings, C2-30 alkenyl, phenyi-Ci - 6 alkyl, 
naphthyl-Ci - & alkyl or Ci-21 aryl, which may have 1 to 4 substituents, or (2) -CONR 1 *R 15 or -CO- 
R 19 ), 



R 12 , R u and R 15 are independently (1) hydrogen, or (2) C1-30 straight or branched alkyl, C3-8 
cycloalkyl, saturated bi- or tricyclic hydrocarbon group formed by fusing 5 to 8 membered rings, 
C2-30 alkenyl, phenyl-Ci-G alkyl, naphthyl-Ci - & alkyl or C4-24 aryl, which may have 1 to 4 
substituents; 

R 13 , R 16 , R 17 , R 18 and R 19 are independently C1-30 straight or branched alkyl, C3-8 cycloalkyl, 
saturated bi- or tricyclic hydrocarbon group formed by fusing 5 to 8 membered rings, C2-30 alkenyl, 
phenyl-Ci-6 alkyl, naphthyl-Ci -s alkyl or C4-24 aryl, 

R 10 and R 3 may bind together to form a ring of the formula: 



(wherein q is an integer of 2 or 3; A and R 11 are as defined above), or R 10 may bind to R 4 , R e or R 8 
to form a ring of the formula: 



(wherein q and r are an integer of 2 or 3, respectively; and R 11 is as defined above), or R 10 may bind 
to R 11 to from a ring of the formula: 



wherein 








94 



BNSDOCID: <EP 



0471236A1 J_* 



EP 0 471 236 A1 



0, 




R 14 and R 15 together with the adjacent nitrogen atom may form 1-aziridinyl, 1-azetidinyl, 
piperidino, perhydro-1 -azepinyl, perhydro-1 -azocynyl, morpholino, thiomorpholino, 1-piperazinyl, 3- 
thiazolidinyL 1-indolyi. perhydro-1 -indolyl. 2-isoindolyl. perhydro-2-isoindolyl. 1 .2.3.4-tetrahydro-1- 
quinolyl, 1 ,2,3,4-tetrahydro-2-isoquinolyl, perhydro-1-quinolyl, perhydro-2-isoquinolyl, 3-azabicyclo- 
[3.2.2]non-3-yl, 9-carbozolyl, 10-acridanyl, 




10,11-dihydro-5H-5-dibenztb,f]azepinyl, 5,6,1 1 ,12-tetrahydro-5-dibenz[b,f]azocinyl, 1 ,2,3,4-tetrahydro- 
9-carbazolyl, 10-phenoxadinyl or 10-phenothiadinyl; 

said the substitutent of Ci -6 alkyl is halogen, nitro, amino, N-mono Ci -6 alkylamino, N,N-di 
Ci-6 alkylamino, 4 to 7 membered cyclic amino, Ci - G alkoxy, C&-10 aryloxy, carbamoyl, cyano, 
hydroxy, carboxy, Ci -6 alkoxycarbonyl or Ci-& alkylcarbonyl, 

said the substitutent of Ci-3 0 alkyl alkenyl is (1) C3-8 cycloalkyl, (2) phenyl optionally 
substituted with 1 to 4 substituents selected from Ci -6 alkyl, Ci -& alkoxy, hydroxy, nitro and 
halogen, (3) naphthyl, (4) halogen, (5) cyano, (6) oxo or (7) Ci-& alkoxy; 

said substitutent of C 3 - 8 cycloalky! or saturated bi- or tricyclichydrocarbon is Ci-g afkyl. 
halogeno Ci -6 alkyl, hydroxy Ci-g alkyl, acyloxy Ci -& alkyl, C1-6 alkoxy-Ci-& alkyl, Ci -e alkoxy, 
halogeno Ci -& alkoxy, C1-& alkoxycarbonyl-Ci -e alkoxy, Ci -& alkenyloxy, aralkyloxy, Ci-& alkoxy- 
C1-6 alkoxy, C1-& alkoxycarbonyl, carboxy, carbamoyl, N,N-di Ci-e, alkylcarbamoyl, N-C1 -6 alkyl- 
carbamoyl, halogen, cyano, nitro, hydroxy, acyloxy, amino, C1-& alkylsulfonylamino, acyamino, C1-& 
alkoxycarbonylamino, acyl, mercapto, C1-6 alkylthio, Ci-g alkylsulfinyl, Ci -& alkylsulfonyl or oxo; 

said substituent of pheny-Ci alkyl or naphthyl-Ci -& alkyl is halogen, Ci- 6 alkyl, Ci alkoxy, 
nitro, cyano, hydroxy, C1-& alkoxycarbonyl, carbamoyl or C1-6 alkylcarbamoyl; 

said substituent of C4-24 aryl is halogen, Ci -6 alkyl, Ci-& alkoxy, nitro, cyano, oxo, hydroxy, 
amino, Ct- & alkoxycarbonyl, carbamoyl or Ci- 6 alkylcarbamoyl; 

tho op^nnnlly prnfprfpH amino rjroi.jp of P* s>nH R? i<~ n^'no -irv , " m ^ r /'A^cnoin ^r\'l nmur 



Use of a comoound of the formula (I) as defined in claim 1 or a pharmaceutical^ acceptable salt or 
solvate thereof in the preparation of a calmodulin inhibitory composition. 



EP 0 471 236 A1 




R 1 



<!' ) 



X-A-B 1 



wherein X is S, S(O), S(0) 2l O or NR 3 (wherein R 3 is a hydrogen or an optionally substituted 
hydrocarbon group); A is a divalent straight or branched straight or branched C1-15 hydrocarbon group 
which may contain an ethereal oxygen at any possible position and may have a substituent at a 
branched part of the hydrocarbon group; B 1 is an amino group acylated by an acyl group derived from 
a carboxylic acid having 2 or more carbon atoms, a sulfonic acid, a carbamic acid or a thiocarbamic 
acid; and R 1 and R 2 are the same or different and are a hydrogen, an optionally substituted 
hydrocarbon group, a halogen, a nitro group, a nitroso group, an optionally protected amino group, a 
lower alkoxycarbonyl group or a lower alkylcarbamoyl group, or a salt or solvate thereof. 

A compound according to claim 4, wherein 

each optionally substituted hydrocarbon group of R 1 and R 2 is independently Ci- 6 alkyl, phenyl- 
C1-6 alkyl, naphthyl-Ci -6 alkyl or CU-2* aryl, which may have 1 to 4 substituents; 

Optionally substituted hydrocarbon group of R 3 is Ci - 5 alkyl phenyl-Ci- 6 alkyl or naphthyl-Ci - 6 
alkyl, which may have 1 to 4 substituents; 

A is a group of the formula: 



wherein all the symbols are as defined in claim 2, -CH2CH2OCH2CH2- or a group of the formula: 



(wherein R 10 ' is (1) hydrogen, or (2) Ci -30 straight or branched alkyl, C 3 -s cycloalkyl, saturated bi- or 
tricyclic hydrocarbon group formed by fusing 5 to 8 membered rings, C2-30 alkanyl, phenyl C1-6 alkyl, 
naphthyl Ci -& alkyl or C*- 2 * aryl, which may have 1 to 4 substituents, or (3) -CO-R 12 , -S0 2 R 13 , 
-CONR u R 15 and -CS-NR 1 *R 15 ; 

said substituent of phenyl-Ci-6 alkyl or naphthyl-Ci -6 alkyl is halogen, Ci- e alkyl, Ci - s alkoxy, 
nitro, cyano, hydroxy, Ci- 6 alkoxycarbonyl, carbamoyl or C1-6 alkylcarbamoyl; 

said substituent of C4-24 aryl is halogen, C1-6 alkyl, C1-6 alkoxy, nitro, cyano, oxo, hydroxy, 
amino, C1-6 alkoxycarbonyl, carbamoyl or Ci-& alkylcarbamoyl; and 

R 11 is -CO-R 15 , -S0 2 R 17 , -CO-NR 1 *R 15 or -CS-NR U R 1 *); 

wherein R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are as defined in claim 2 

said the substitutent of Ci-& alkyl is halogen, nitro, amino, N-mono C1-6 alkylamino, N,N-di C1-& 
alkylamino, 4 to 7 membered cyclic amino, Ci - 6 alkoxy, Cs-io aryloxy, carbamoyl, cyano, hydroxy, 
carboxy, Ci - 6 alkoxycarbonyl or Ci -6 alkylcarbonyl; 

said substituent of phenyl-Ci- & alkyl or naphthyl-d - 6 alkyl is halogen, Ci-& alkyl, Ci ~ 6 alkoxy, 




R 6 R8 





(wherein o and p are integers of 0 to 5); 
B 1 is a group of the formula: 



-NR 10 'R ir 



96 



71236A1. I. 



EP 0 471 236 A1 



nitro, cyano, hydroxy, -s alkoxycarbonyl, carbamoyl or C:-6 alkylcarbamoyl; 

said substituent of C<- 2 4 aryl is halogen, Ci- & alkyl, C: - 6 alkoxy, nitro, cyano, oxo, hydroxy, 
amino, Ci -& alkoxycarbonyl, carbamoyl or Ci -6 alkylcarbamoyl; 

the optionally protected amino group of FT and R 2 is amino, acylamino (wherein the acyl group is 
5 the same as that of FT 1 ) or tritylamino; and 

the lower alkyoxycarbonyl and lower alkylcarbamoyl of R 1 and R 2 are Ci-& alkoxycarbonyl and 
Ci- & alkylcarbamoyl, respectively. 

6. A compound according to claim 4, wherein ET is -NH-SO2R 17 (wherein R 17 is as defined in claim 2). 

10 

7. A compound according to claim 4, wherein X is S or O, and B 1 is -NH-SO2R 17 (wherein R 17 is as 
defined in claim 2). 



8. A compound according to claim 4 which is 
75 5-[2-(methylsulfonylamino)ethylthio]imidazo[1 ,2-a]pyridine, 

5-[2-(tnfluoromethylsulfonylamino)ethylthio]imidazo[1 .2-a]pyridine : 
5-[3-(methylsulfonylamino)propyloxy]imidazo[1 ,2-a]pyridine, 
5-[3-(tnfluoromethylsulfonylamino)propyloxy]imidazo[1 ,2-a]pyridine, 
5-[3-(methylsulfonylamino)propy!thio]imidazo[1 ,2-a]pyridine, or 
20 5-[3-(trtfluoromethylsulfonylamino)propylthio]imidazo[1 ,2-a]pyridine. 



9- A calmodulin inhibitory composition comprising a compound of the formula (V) as defined in claim 4 or 
a pharmaceutical^ acceptable salt or solvate thereof, and a pharmaceutical^ acceptable carrier, diluent 
or excipient. 

25 

10. Use of a compound of the formula (I') as defined in claim 4 or a pharmaceutical^ acceptable salt or 
solvate thereof in the preparation of a calmodulin inhibitory composition. 



11. A compound of the formula (I"): 

30 




40 wherein X is S, S(O), S(0>2, O or NR 3 (wherein R 3 is hydrogen or an optionally substituted hydrocarbon 

group); A is a divalent straight or branched C1-15 hydrocarbon group which may contain an ethereal 
oxygen at any possible position and may have a substituent at a branched part of the hydrocarbon 
group; B 2 is an acylated amino group, and the nitrogen atom of the amino group of B 2 connects with 
the carbon atom of A or R 3 to form a ring; and R 1 and R 2 are the same or different and are a hydrogen, 

45 an optionally substituted hydrocarbon group, a halogen, a nitro group, a nitroso group, an optionally 

protected amino group, a lower alkoxycarbonyl group or a lower alkylcarbamoyl group, or a salt or 
solvate thereof. 



optionally substituted nydrocaroor group H ' is U- aiKy*. pneny.-C-- fe a;ky -j' naphtfy • --1 
a ! kyl, which may have 1 to 4 substituents; 
A is a group of the formula: 



EP 0 471 236 A1 



R 4 R 6 R 8 




wherein all the symbols are defined in claim 2, a group of the formula: -CH2CH2OCH2CH2- or a group 
of the formula: 



wherein all the symbols are defined in claim 2 

said the substitutent of C1 -6 alkyl is halogen, nitro, amino, N-mono C1-6 alkylamino, N,N-di Ci-e 
alkylamino, 4 to 7 membered cyclic amino, C1-6 alkoxy, C6-10 aryloxy, carbamoyl, cyano, hydroxy, 
carboxy, C1 -e alkoxycarbonyl or C\ -6 alkylcarbonyl; 

said substituent of phenyl-Ci-6 alkyl or naphthyi-Ci - 6 alkyl is halogen, C1 -6 alkyl, C1 -6 alkoxy, 
nitro, cyano, hydroxy, C1 -g alkoxycarbonyl, carbamoyl or C1 - e alkylcarbamoyl; 

said substituent of C4-24 aryl is halogen, C1 -& alkyl, C1-& alkoxy, nitro, cyano, oxo, hydroxy, 
amino, C1-6 alkoxycarbonyl, carbamoyl or C1-6 alkylcarbamoyl; 

the optionally protected amino group of R 1 and R 2 is amino, acylamino (wherein the acyl group is 
the same as that of R 11 ) or tritylamino; and 

the lower alkyoxycarbonyl and lower alkylcarbamoyl of R 1 and R 2 is C1 -& alkoxycarbonyl and Ci- e 
alkylcarbamoyl. 

13. A compound according to claim 11, wherein X is S or O. 

14. A compound according to claim 11 which is 

5-[1 -(methylsulfonyl)-4-piperidylthio]imidazo[1 ,2-a]pyridine, 
5-[1-(trifluoromethyl)"4-piperidylthio]imidazo[1 ,2-a]pyridine. 

15. A calmodulin inhibitory composition comprising a compound of the formula (I") as defined in claim 11, 
or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical^ acceptable carrier, 
diluent or excipient. 

16. Use of a compond of the formula (l M ) as defined in claim 1 1 or a pharmaceutically acceptable salt or 
solvate thereof in the preparation of a calmodulin inhibitory composition. 

17. A compound of the formula (I'"): 




(wherein o and p are integers of 0 to 5); 
B 2 is a group of the formula: 



-N 





98 



EP 0 471 236 A1 




wherein X is S, S(0), S(0>2 or NR 3 (wherein R 3 is hydrogen or an optionally substituted hydrocarbon 
group); A is a divalent straight or branched C1-15 hydrocarbon group which may contain an ethereal 
oxygen at any possible position and may have a substituent at a branched part of the hydrocarbon 
group; R 1 and R 2 are the same or different and are a hydrogen, an optionally substituted hydrocarbon 
group, a halogen, a nitro group, a nitroso group, an optionally protected amino group, a lower 
alkoxycarbonyl group or a lower alkyl carbamoyl group; and B 3 is a hydroxyl group acylated by an acyl 
group derived from a carboxylic acid or a N-hydrocarbon substituted carbamic acid, or its salt or 
.solvate 



A compound according to claim 17, wherein 

each optionally substituted hydrocarbon group of R 1 and R 2 is independently C1 alkyl, phenyl- 
C1-6 alkyl, naphthyl-Ci -s alkyl or C4-24 aryl, which may have 1 to 4 substituents; 

optionally substituted hydrocarbon group of R 3 is C1 -6 alkyl, phenyl-Ci- 6 alkyl or naphthyl-Ci 
alkyl, which may have 1 to 4 substituents; 

A is a group of the formula: 



R R° R° 

I I I 

-<c)i-<c) m -(C) n - 

R 5 R 7 R 9 



wherein all the symbols are defined in claim 2, a group of the formula: -CH2CH2OCH2CH2- or a group 
of the formula: 



-<C„,)o<3> CCH ' )P " 

(wherein 0 and p are integers of 0 to 5); 
B 3 is -0-CO-NR lS R 16 or -O-CO-R 19 , 
wherein R 15 , R 16 and R 19 are defined in claim 2 

said the substitutent of Ci-s alkyl is halogen, nitro, amino, N-mono C1-6 alkylamino, N.N-di Ci-s 
alkylamino, 4 to 7 membered cyclic amino, Ci-& alkoxy, C 6 -io aryloxy, carbamoyl, cyano, hydroxy, 
carboxy, C1 -6 alkoxycarbonyl or C<-6 alkylcarbonyl; 

said substituent of phenyl-Ci-& alkyl or naphthyi-Ci - 6 alkyl is halogen, C1 -& alkyl, C1-6 alkoxy, 



tne same as that of R" or tritylamino, ana 

the lower alkyoxycarbonyl and lower alkylcarbamoyl of R' and R : are C- - 1) alkoxycarbcny 1 and 
C1-6 alkylcarbamoyl respectively. 



EP 0 471 236 A1 

20. A compound according to claim 17 which is 

5-[2-(methylcarbamoyloxy)ethylthio]innidazo[1 ,2-a]pyridine, or 
5-[2-[3-(hydroxy)propy!carbamoyloxy]ethylthio]imidazo[1 ,2-a]pyridine. 

5 21. A calmodulin inhibitory composition comprising a compound of the formula (I'") as defined in claim 17, 
or a pharmaceutical^ acceptable salt or solvate thereof, and a pharmaceutical^ acceptable carrier, 
diluent or excipient. 

22. Use of a compound of the formula (I'") as defined in claim 17, or a pharmaceutical^ acceptable salt or 
70 solvate thereof in the preparation of a calmodulin inhibitory composition. 

23. A process for producing a compound according to claim 4 or 11 or a salt or solvate thereof which 
comprises; 

reacting a compound of the formula: 

j R 2 

25 wherein all the symbols are as defined in claim 2 with a compound of the formula Q 1 -NR 14 R 15 , G 1 -CO- 

(0) q -R 15 or G 2 -S0 2 R 17 wherein Q 1 is PhO-CO-, G-CO or G-CS (wherein Ph is a phenyl group and G is 
a halogen), G 1 is a halogen or R l6 (0) q -CO-0- (wherein q is 0 or 1), q is 0 or 1, G 2 is a halogen or 
R 17 S0 2 O, and the other symbols are defined in claim 2. 

30 24. A process for producing a compound according to claim 4 or a salt or solvate thereof which comprises; 
reacting a compound of the formula: 



35 



20 




40 



wherein E is a halogen and the other symbols are as defined in claim 4, with a compound of the 
formula HX 1 -A-B 1 wherein X 1 is S, O or NR 3 and the other substituents are as defined in claim 4, or 
when, X is S or 0, reacting a compound of the formula: 



45 



50 




wherein X 2 is S or 0 and the other symbols are as defined in claim 4 with a compound of the formula 
E 1 -A-B 1 wherein E 1 is a leaving group, and the other symbols are as defined in claim 4, or 
55 when X is S(O) or S(0)2, oxidizing a compound of the formula: 



100 



BNSDOCID: <EP__ _0471 236A< _!_•> 



EP 0 471 236 A1 




70 



wherein all the symbols are as defined in claim 4. 

25. A process for producing a compound according to claim 1 1 or a salt or solvate which comprises 
reacting a compound of the formula: 



75 



20 



R 2 



25 



wherein E is a halogen and the other symbols are as defined in claim 11, with a compound of the 
formula HX 1 -A-B 2 wherein X 1 is S, O or NR 3 and the other symbols are as defined in claim 11, or 

when the nitrogen atom of the amino group of B 2 forms a ring with a carbon atom of A, reacting a 
compound of the formula: 



30 




35 wherein X 2 is S or O and the other symbols are as defined in claim 1 1 with a compound of the formula 

E 1 -A-B 2 wherein E 1 is a leaving group, and the other symbols are as defined in claim 11 or 
when X is S(O) or S(0) 2 . oxidizing a compound of the formula: 



40 



45 



9>< 

S-A-B 2 



wherein all the fv^hels af° a c rfefinnH in r-\p.\m. 1 1 



EP 0 471 236 A1 




X-A-OH 



10 wherein the symbols are as defined in claim 17 with a compound of the formula CT-NR^R 16 or G^CO- 

(0) q -R 19 wherein Q\ G 1 and q are defined in claim 23, and the other symbols are defined in claim 2, or 
reacting a compound of the formula: 




25 



wherein E is a halogen and the other symbols are as defined in claim 17, with a compound of the 
formula HX 1 -A-B 3 wherein X 1 is S, O or NR 3 and the other symbols are as defined in claim 17, or 
reacting a compound of the formula: 



30 



35 wherein X 2 is S or O and the other symbols are as defined in claim 17 with a compound of the formula 

E 1 -A-B 3 wherein E 1 is a leaving group, and the other symbols are defined in claim 17 or 
when X is S(O) or S(0) 2 , oxidizing a compound of the formula: 




45 S-A-B 3 

wherein all the symbols are as defined in claim 17. 
so 27. An angiogenesis inhibitory composition comprising a compound of the formula (1): 



55 



102 



BNSDOCID <EP 0471236A1_I_> 



EP 0 471 236 A1 



5 




R c 

70 

wherein A' is a divalent straight or branched Ci-is hydrocarbon group which may contain ethereal 
oxygen at any possible position and a branched part of the hydrocarbon group may be substituted; R a 
and R b are the same or different and are a hydrogen, an optionally substituted hydrocarbon group, a 
halogen, a nitro group, a nitroso group, an optionally protected amino group, a lower alkoxycarbonyl 
75 group or a lower alkyl carbamoyl group; R c is a hydrogen or an optionally substitued hydrocarbon 

group or may form a ring together with the carbon atom of A; and R d Is an optionally substituted 
hydrocarbon group, or a pharmaceutical^ acceptable salt thereof, and a pharmaceutical^ acceptable 
carrier, diluent or excipient. 

20 28. An angiogenesis inhibitory composition according to claim 27, wherein 
A' is (a) a group of the formula: 

R<3 r 1 

I I 

(C) y-(C) 2 - 

R h RJ 



25 



-(C) - 



30 (wherein x, y and z are integers of 0 to 5, respectively; each of R e , R\ R 9 , R h , R 1 and R j is (1) a 

hydrogen, or (2) a Ci-t alkyl, C2-& alkenyl, which may have 1 to 5 substituents, or (3) phenyl-Ci-& 
alkyl, naphthyl-Ci - 6 alkyl, C&-1* aryl, or an aromatic monocyclic or bicyclic heterocyclic group 
containing 1 to 4 hetero atoms selected from sulfur, oxygen and nitrogen, which may have 1 to 4 
substituents, or R e and R' or R 9 and R h or R' and R J may bind together to form C 3 -a cycloalkane 

35 ring, or R e or R 9 may bind together with R j or R j to form C 3 -s cycloalkane ring, 

(b) a group of the formula: -CH2CH2OCH2CH2- or 

(c) the formula: 



40 



CCHOb" 

/ / .,.-4 \ 

-(CH,)a- 



wherein a and b are integers of 0 to 5, respectively; 
45 each optionally substituted hydrocarbon group of R a and R b is a Ci- fe alkyl, C 2 -& alkenyl, 

phenyl-Ci-s alkyl, naphthyl-Ci -s alkyl or Ce-M aryl group, which may have 1 to 4 substituents; 

the lower alkoxycarbonyl and lower alkylcarbamoyl of R a and R b are C1-& alkoxycarbonyl and 

r* 1 alkv'rp.rb^rnnv' rocnor + iwo 1 '^ 



each optionally substituted Hydrocarbon group o* K and R : is U- al<yi. C:» - s oycicaiky:. C. - 
a konyi, phenyl-C« -f, atkyl, naphthyl-C- alkyl or Cc,--* aryl, which may have 1 to 5 substituents, 
R c and R R or R'. or R c and R g or R r , or R c and R' or R J may bind together to form 



EP 0 471 236 A1 



20 



CCH2) 0\ nu / (CH2) Q\m 

w N— — CH 2 — ( w N 



(CH,)/ , \cH 2 )/ 



— CH 2 CH 2 -< W ,N- 
" N (CH 2 ) R / 



wherein Q and R are interger of 2 or 3, respectively; 

said substituent of Ci-& alkyl, C 3 - 8 cycloalkyl or C 2 -g alkenyl is halogen, nitro, amino, N-mono 
75 C1-6 alkylamino, IM,N-di Ci-& alkylamino, Cw cyclic amino, C1-6 alkoxy, phenoxy, 1-naphthoxy, 2- 

naphthoxy, carbamoyl, cyano, hydroxy, carboxy, C1 -e alkoxycarbonyl or C1-6 alkylcarbamoyl; 

said substitutent of phenyl Ci-& alkyl, naphthyl-Ci - 6 alkyl or heterocyclic group is halogen, 
C1-6 alkyl, C 2 -& alkenyl, Ci-s alkoxy, nitro, cyano, oxo, hydroxy, amino, C1 -& alkoxycarbonyl, 
carbamoyl or Ci -g alkylcarbamoyl. 



29. An angiogenesis inhibitory composition according to claim 27, wherein A' is ethylene, R c is hydrogen 
- & alkyl or C 2 -& alkenyl. 



30. An angiogenesis inhibitory composition according to claim 27, wherein the compound is 
25 5-[2-(isopropyloxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine, 

5-[2-(ethoxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine, 
5_[2-(methoxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine, 
5-[2-(propyloxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine, or 
5-[2-(allyloxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine. 

30 

31. Use of a compound of the formula (1) as defined in claim 27 or a pharmaceutical^ acceptable salt or 
solvate thereof in the prepartion of an angiogenesis inhibitory composition. 



35 



40 



45 



50 



55 



104 



BMSDOOD; <EP 0471236A1 I > 



J 



European Patent 
Office 



EUROPEAN SEARCH REPORT 



Application Number 



DOCUMENTS CONSIDERED TO BE RELEVANT 



Category 



D, A 



D , A 



Citation of document with indication, where appropriate, 
of relevant passages 



EP - A2/A3 ~ 0 006 614 
(MERCK & CO INC. ) 

* Claims 1,7,8; page 9, 
9 - page 10, line 36 

DE - Al - 2 820 938 
(MERCK & CO INC. ) 

* Claims 1, 28 •* 



line 



EP - Al 



0 185 34 5 



(DR. KARL THOMAE GESMBH) 
* Claims 1,2-4,7,8 * 



US - A - 4 833 149 
(J. B. PRESS) 

* Abstract; claims 1-8; column 
2, lines 1-39 * 



Relevant 
to claim 



1-22, 
27-31 



1-22, 
27-31 



1-22, 
27-31 



1-22, 
27-31 



EP 91112798.3 



CLASSIFICATION OF THE 
APPLICATION Out. CL5) 



61 
61 

07 



31/435 
31/44 
471/04 



TECHNICAL FIELDS 
SEARCHED (Int. CL5) 



A 61 K 31/00 
C 07 D 471/00 
C 07 D 487/00 



CATEGORY OF CITED DOd.'Mt.MS 



X : particularly relevant If taken alone 
Y : particularly relevant if combined *ith another 
document of the same C2'.r-^r% 



I : theory or principle undetivlng the Invention 
E : earlier patent document, but published od, or 

after the filing dale 
D : document died In the application 
I. * document cited for ether reason